Bicyclic heterocycles as HIV integrase inhibitors

ABSTRACT

The invention encompasses a series bicyclic pyrimidinone compounds of Formula I which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Non-Provisionalapplication Ser. No. 11/126,891 filed May 11, 2005, and claims thebenefit of U.S. Provisional Application Ser. No. 60/603,371 filed Aug.20, 2004 and 60/575,513 filed May 28, 2004.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) has been identified as theetiological agent responsible for acquired immune deficiency syndrome(AIDS), a fatal disease characterized by destruction of the immunesystem and the inability to fight off life threatening opportunisticinfections. Recent statistics (UNAIDS: Report on the Global HIV/AIDSEpidemic, December 1998), indicate that as many as 33 million peopleworldwide are infected with the virus. In addition to the large numberof individuals already infected, the virus continues to spread.Estimates from 1998 point to close to 6 million new infections in thatyear alone. In the same year there were approximately 2.5 million deathsassociated with HIV and AIDS.

There are currently a number of antiviral drugs available to combat theinfection. These drugs can be divided into three classes based on theviral protein they target and their mode of action. In particular,saquinavir, indinavir, ritonavir, nelfmavir and amprenavir arecompetitive inhibitors of the aspartyl protease expressed by HIV.Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavirare nucleoside reverse transcriptase inhibitors that behave as substratemimics to halt viral cDNA synthesis. The non-nucleoside reversetranscriptase inhibitors, nevaripine, delavirdine and efavirenz inhibitthe synthesis of viral cDNA via a non-competitive (or uncompetitive)mechanism. Used alone these drugs are effective in reducing viralreplication. The effect is only temporary as the virus readily developsresistance to all known agents. However, combination therapy has provenvery effective at both reducing virus and suppressing the emergence ofresistance in a number of patients. In the US, where combination therapyis widely available, the number of HIV-related deaths has declined(Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.;Further, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J.Med. 1998, 338, 853–860).

Unfortunately, not all patients are responsive and a large number failthis therapy. In fact, approximately 30–50% of patients ultimately failcombination therapy. Treatment failure in most cases is caused by theemergence of viral resistance. Viral resistance in turn is caused by therapid turnover of HIV-1 during the course of infection combined with ahigh viral mutation rate. Under these circumstances incomplete viralsuppression caused by insufficient drug potency, poor compliance to thecomplicated drug regiment as well as intrinsic pharmacological barriersto exposure provides fertile ground for resistance to emerge. Moredisturbing are recent findings which suggest that low-level replicationcontinues even when viral plasma levels have dropped below detectablelevels (<50 copies/ml) (Carpenter, C. C.; Cooper, D. A.; Fischl, M. A.;Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.; Jacobsen,D. M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D. D.; Saag, M. S.;Schechter, M.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.;Volberding, P. A. JAMA 2000, 283, 381–390). Clearly there is a need fornew antiviral agents, preferably targeting other viral enzymes to reducethe rate of resistance and suppress viral replication even further.

HIV expresses three enzymes, reverse transcriptase, an aspartylprotease, and integrase. All three are targets for treating AIDS and HIVinfection. HIV integrase catalyzes insertion of the viral cDNA into thehost cell genome, which is a critical step in the viral life cycle. HIVintegrase inhibitors belonging to a class of diketo acid compoundsprevented viral integration and inhibited HIV-1 replication in cells(Hazuda et al. Science 2000, 287, 646). And recently, HIV integraseinhibitors have been accepted into clinical trials for treating AIDS andHIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Paisand Burke Drugs Fut. 2002, 27, 1101).

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I, includingpharmaceutically acceptable salts and solvates, their pharmaceuticalcompositions, and their use in inhibiting HIV integrase and treatingthose infected with HIV or AIDS.

One aspect of the invention are compounds of Formula I

wherein:

-   R¹ is C₁₋₆(Ar¹)alkyl, C₁₋₆(Ar¹)(CON(R⁸)(R⁹))alkyl,    C₁₋₆(Ar¹)(CO₂R¹⁴)alkyl, C₁₋₆(Ar¹)hydroxyalkyl, or C₁₋₆(Ar¹)oxyalkyl;-   R² is hydrogen, C₁₋₆alkyl, or OR¹⁴;-   R³ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₅₋₇cycloalkenyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,    C₁₋₆haloalkoxy, N(R⁸)(R⁹), NHAr², N(R⁶)SO₂R⁷, N(R⁶)COR⁷, N(R⁶)CO₂R⁷,    OCOR⁷, OCO₂R⁷, OCON(R⁸)(R⁹), OCH₂CO₂R⁷, OCH₂CON(R⁸)(R⁹), COR⁶,    CO₂R⁶, CON(R⁸)(R⁹), SOR⁷, S(═N)R⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), PO(OR⁶)₂,    C₂₋₄(R¹²)alkynyl, R¹³, Ar², or Ar³;-   R⁴ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆haloalkyl, C₁₋₆haloalkoxy, or N(R⁶)(R⁶);-   R⁵ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆haloalkyl, C₁₋₆haloalkoxy, or N(R⁶)(R⁶);-   R⁶ is hydrogen, C₁₋₆alkyl, or C₃₋₇cycloalkyl;-   R⁷ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   R⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl    or C₁₋₆(C₁₋₆dialkylamino)alkyl;-   R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl    or C₁₋₆(C₁₋₆dialkylamino)alkyl; or-   N(R⁸)(R⁹) taken together is azetidinyl, pyrrolidinyl,    (R¹⁰)-piperidinyl, N—(R¹¹)-piperazinyl, morpholinyl,    thiomorpholinyl, or dioxothiazinyl;-   R¹⁰ is hydrogen, C₁₋₆alkyl, or C₁₋₆hydroxyalkyl;-   R¹¹ is hydrogen, C₁₋₆alkyl, C₃₋₇cyclolkyl, COR⁶, or CO₂R⁶;-   R¹² is hydrogen, hydroxy, N(R⁶)(R⁶), SO₂R⁷, OSO₂R⁷, or    dioxothiazinyl;-   R¹³ is azetidinonyl, pyrrolidinonyl, valerolactamyl, caprolactamyl,    maleimido, oxazolidonyl, or dioxothiazinyl, and is substituted with    0–1 substituents selected from the group consisting of    hydroxymethyl, acetoxymethyl, and aminomethyl;-   R¹⁴ is hydrogen or C₁₋₆alkyl;

-   Ar² is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,    imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl,    thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl,    hydroxypyridinyl, quinolinyl, isoquinolinyl, or indolyl, and is    substituted with 0–2 substituents selected from the group consisting    of halo, cyano, benzyl, C₁₋₆alkyl, C₁₋₆alkoxy, N(R⁸)(R⁹),    CON(R⁸)(R⁹), CO₂R⁶, CONHSO₂N(R⁶)(R⁶), CONHSO₂N(R⁶)(phenyl), and    CONHSO₂N(R⁶)(halophenyl);-   Ar³ is phenyl substituted with 0–2 substituents selected from the    group consisting of halo, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,    (C₁₋₆alkoxy)methyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, N(R⁸)(R⁹),    CON(R⁶)(R⁶), and CH₂N(R⁸)(R⁹), or is dioxolanylphenyl; and-   X—Y-Z is C(R¹⁴)₂OC(R¹⁴)₂, C(R¹⁴)₂OC(R¹⁴)₂C(R¹⁴)₂, or    C(R¹⁴)₂C(R¹⁴)₂C(R¹⁴)₂C(R¹⁴)₂;    or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a compound of Formula I where R¹ isC₁₋₆(Ar¹)alkyl.

Another aspect of the invention is a compound of Formula I where R¹ is

Another aspect of the invention is a compound of Formula I where R¹ is

Another aspect of the invention is a compound of Formula I where R² ishydrogen.

Another aspect of the invention is a compound of Formula I where R³ ishydrogen, halo, N(R⁸)(R⁹), N(R⁶)COR⁷, OCON(R⁸)(R⁹), CON(R⁸)(R⁹), SOR⁷,SO₂R⁷, SO₂N(R⁶)(R⁶), PO(OR⁶)₂, R¹³, or Ar².

Another aspect of the invention is a compound of Formula I where X—Y-Zis C(R¹⁴)₂OCH₂, C(R¹⁴)₂OCH₂CH₂, or C(R¹⁴)₂OCH₂CH₂CH₂.

Another aspect of the invention is a compound of Formula I where X—Y-Zis CH₂OCH₂, C(CH₃)HOCH₂, C(CH₃)₂OCH₂, CH₂OCH₂CH₂, C(CH₃)HOCH₂CH₂,C(CH₃)₂OCH₂CH₂, CH₂OCH₂CH₂CH₂, C(CH₃)HOCH₂CH₂CH₂, or C(CH₃)₂OCH₂CH₂CH₂.

Another aspect of the invention is a compound of Formula I selected fromthe group of structures consisting of

Another aspect of the invention is a method for making a compound offormula II

where:

-   R¹ is C₁₋₆(Ar¹)alkyl;-   R² is hydrogen;-   R³ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₅₋₇cycloalkenyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,    C₁₋₆haloalkoxy, N(R⁸)(R⁹), NHAr², N(R⁶)SO₂R⁷, N(R⁶)COR⁷, N(R⁶)CO₂R⁷,    OCOR⁷, OCO₂R⁷, OCON(R⁸)(R⁹), OCH₂CO₂R⁷, OCH₂CON(R⁸)(R⁹), COR⁶,    CO₂R⁶, CON(R⁸)(R⁹), SOR⁷, S(═N)R⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), PO(OR⁶)₂,    C₂₋₄(R¹²)alkynyl, R¹³, Ar², or Ar³;-   R⁴ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆haloalkyl, C₁₋₆haloalkoxy, or N(R⁶)(R⁶);-   R⁵ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆haloalkyl, C₁₋₆haloalkoxy, or N(R⁶)(R⁶);-   R⁶ is hydrogen, C₁₋₆alkyl, or C₃₋₇cycloalkyl;-   R⁷ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   R⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl    or C₁₋₆(C₁₋₆dialkylamino)alkyl;-   R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl    or C₁₋₆(C₁₋₆dialkylamino)alkyl; or-   N(R⁸)(R⁹) taken together is azetidinyl, pyrrolidinyl,    (R¹⁰)-piperidinyl, N—(R¹¹)-piperazinyl, morpholinyl,    thiomorpholinyl, or dioxothiazinyl;-   R¹⁰ is hydrogen, C₁₋₆alkyl, or C₁₋₆hydroxyalkyl;-   R¹¹ is hydrogen, C₆alkyl, C₃₋₇cyclolkyl, COR⁶, or CO₂R⁶;-   R¹² is hydrogen, hydroxy, N(R⁶)(R⁶), SO₂R⁷, OSO₂R⁷, or    dioxothiazinyl;    R¹³ is azetidinonyl, pyrrolidinonyl, valerolactamyl, caprolactamyl,    maleimido, oxazolidonyl, or dioxothiazinyl, and is substituted with    0–1 substituents selected from the group consisting of    hydroxymethyl, acetoxymethyl, and aminomethyl;-   R¹⁴ is hydrogen or C₁₋₆alkyl;

-   Ar² is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,    imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl,    thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl,    hydroxypyridinyl, quinolinyl, isoquinolinyl, or indolyl, and is    substituted with 0–2 substituents selected from the group consisting    of halo, cyano, benzyl, C₁₋₆alkyl, C₁₋₆alkoxy, N(R⁸)(R⁹),    CON(R⁸)(R⁹), CO₂R⁶, CONHSO₂N(R⁶)(R⁶), CONHSO₂N(R⁶)(phenyl), and    CONHSO₂N(R⁶)(halophenyl); and-   Ar³ is phenyl substituted with 0–2 substituents selected from the    group consisting of halo, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,    (C₁₋₆alkoxy)methyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, N(R⁸)(R⁹),    CON(R⁶)(R⁶), and CH₂N(R⁸)(R⁹), or is dioxolanylphenyl;    comprising reacting a compound of the structure

where R¹⁵ is C₁₋₆alkyl with a compound of the formulaC₁₋₆(Ar¹)alkylamine under basic conditions.

Another aspect of the invention is the method for making a compound ofFormula II where the base is a C₁₋₄trialkylamine, C₁₋₄dialkylamine,C₁₋₄alkylamine, or ammonia.

Another aspect of the invention is the method for making a compound ofFormula II where the base is a C₁₋₄trialkylamine or C₁₋₄dialkylamine

Another aspect of the invention is the method for making a compound ofFormula II where the base is a C₁₋₄trialkylamine.

Another aspect of the invention the method for making a compound ofFormula II where the base is triethylamine or diisopropylethylamine.

Another aspect of the invention is the method for making a compound ofFormula II where the conditions include a solvent selected from thegroup consisting of a C₁₋₄alcohol, a (C₁₋₄)dialkyl ether,tetrahydrofuran, dioxane, a (C₁₋₄)-((C₁₋₄)dialkoxy)alkane, DMF, DMSO, ormethylene chloride.

Another aspect of the invention is the method for making a compound ofFormula II further comprising heating a compound of the structure

in a solvent to form a compound of the structure

Another aspect of the invention is a method for making a compound ofFormula II comprising reacting a compound of the structure

where R¹⁵ is hydrogen with a compound of the formula C₁₋₆(Ar¹)alkylamineunder peptide coupling conditions.

Another aspect of the invention is a method for making a compound ofFormula II comprising transforming a compound of the structure

where R¹⁵ is hydrogen into the corresponding acyl chloride and reactingthe acyl chloride with a compound of the formula C₁₋₆(Ar¹)alkylamineunder basic conditions.

Another aspect of the invention is a compound of the structure

where R¹⁴ is hydrogen or C₁₋₆alkyl and R¹⁵ is C₁₋₆alkyl.

Another aspect of the invention is a compound of the structure

where R¹⁴ is methyl and R¹⁵ is methyl or ethyl.

For a compound of Formula I, any scope of R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, Ar¹, Ar², Ar³, and X—Y-Z can beused independently with any scope of any other substituent.

“Alkyl,” “alkoxy,” “hydroxyalkyl,” and related terms with an alkylmoiety include straight and branched configurations. A term such as“C₁₋₆(R)alkyl” means a straight or branched alkyl group of one to sixcarbons substituted with the substituent R. “Haloalkyl” and “halophenyl”include all permutations of halogenated alkyl or phenyl groups, frommonohalo to perhalo. “Aryl” means an aromatic ring system and includescarbocyclic and heterocyclic systems. Some substituents are divalent,such as X—Y-Z. Asymmetric divalent substituents may be attached ineither of the two configurations.

“C₁₋₆(Ar¹)oxyalkyl” means Ar¹ is attached at the oxygen.

“Dioxolanyphenyl” means

“Dioxothiazinyl” means

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

The invention also includes all solvated forms of the compounds,particularly hydrates. Solvates do not contribute significantly to thephysiological activity or toxicity of the compounds and as such functionas pharmacological equivalents. Solvates may form in stoichiometricamounts or may form from adventitious solvent or a combination of both.One type of solvate is hydrate, and some hydrated forms includemonohydrate, hemihydrate, and dihydrate.

Some of the compounds of the invention exist in stereoisomeric forms.The invention includes all stereoisomeric forms of the compoundsincluding enantiomers and diastereromers. An example of enantiomers isshown below. Methods of making and separating stereoisomers are known inthe art.

The invention includes all tautomeric forms of the compounds. An exampleof a tautomeric pair is shown below.

Synthetic Methods

The compounds of this invention can be made by various methods known inthe art including those of the following schemes and in the specificembodiments section. The variables shown in the synthetic schemes aredistinct from and should not be confused with the variables in theclaims or the rest of the specification. The variables in the schemesare meant only to illustrate how to make some of the compounds of thisinvention.

Some compounds can be synthesized from an appropriately substitutedheterocycle I-1 according to Scheme I, where R_(a) and P can serve asprotecting groups (see Greene, T. W. and Wutz, P. G. M. ProtectiveGroups in Organic Synthesis, Second Edition, 1991, John Wiley and Sons,New York). When P is benzyl or substituted benzyl it can be removed byhydrogenolysis (H₂—Pd/C) or acid hydrolysis (trifluoroacetic acid) toyield intermediate I-2. I-2 can be transaminated to I-4 by reaction withamine I-3. In a number of cases this reaction can be carried out byheating I-3 and I-2 together in the presence of base. Alternatively,standard amide coupling reagents can be used to effect the formation ofthe amide bond. When R_(a) is a lower alkyl group, R_(a) can be removedunder ester hydrolysis conditions, such as treatment with NaOH, LiOH, orKOH to deliver the corresponding carboxylic acid I-5. Alternatively,R_(a) can be removed by nucleophilic displacement using NaI. When R_(a)is benzyl and substituted benzyl, R_(a) can be removed byhydrogenolysis. Intermediate I-5 can be coupled using amide bond formingreagents such as BOP, DCC, EDCI, PyBrop, PyBop or other reagents (seeMarch, J. Advanced Organic Chemistry, Fourth Edition 1992 John Wiley &Sons, New York). The resulting intermediate I-6 can be deprotected asdescribed for intermediate I-1.

In Scheme II, intermediate II-3 can be prepared using methods similar tothose described in Sunderland, J. S.; Botta, M.; Aime, S.; Raymond, K.N. Inorg. Chem. (2001), 40, 6756–6756, where II-1 and II-2 arecondensed, to provide intermediate II-3. This reaction is usuallyconducted in the presence of a base such as sodium hydride (NaH), sodiumethoxide (EtONa) or lithium hexamethyldisilazide (LiHMDS). Using themethods described in the reference, II-3 can be condensed with anappropriately substituted amidine II-4 to form II-5. Substituent B canbe a leaving group, such as -halo (Cl, Br or I) or can be converted to aleaving group under appropriate conditions such as by forming thecorresponding methylsulfonate ester. When substituent B is a methylsulphide group it can be treated with iodomethane to form adimethylsulfonium intermediate which is activated towards nucleophilicattack to effect ring closure.

In Scheme III, intermediate II-3 can be condensed with a cyclic-amidineto yield intermediate I-1. Intermediate III-1 can be prepared usingknown methods (see Patai, S. and Rappoport, Z. The Chemistry of Amidinesand Imidates, Volume 2, 1991, John Wiley & Sons, New York).

In Scheme IV, nitrile IV-1, possessing a potential leaving group B, canbe reacted with hydroxylamine to form intermediate IV-2. Thisintermediate can be reacted with a suitably protected alkyne to formIV-3 which can rearrange to from intermediate IV-4 according toliterature methods (Culbertson, T. P. Journal of Heterocyclic Chemistry,1979, 16, 1423–1424).

As shown in Scheme V, 2-(methylthio)ethanol can be alkylated with anappropriate α-haloacetic acid (V-1) wherein X is a leaving group such asCl, Br, OTs, OMs or OTf, to deliver intermediate V-2. Following this,the carboxylic acid can be transformed to the corresponding amidinederivative using known synthetic methods (Geilen et al. TetrahedronLetters 2002, 43, 419–421). As described in the above, the amidine canfurther be reacted with intermediate V-5, in the presence of a base (forexample, sodium ethoxide) affording intermediate V-6. Methylation of thesulphide ether can be accomplished by treating V-6 with iodomethane andthe resulting sulfonium derivative (V-7) treated with base to form thebicyclic template V-8. This intermediate can be used in the synthesis offinal compounds using methods described in Scheme I.

In Scheme VI, 3-methylthiopropanal is converted to dioxolane VI-1 usingwell known chemistry. Treatment with trimethylsilylcyanide (TMSCN), inthe presence of zinc iodide (ZnI₂) produces intermediate VI-2. Reactionwith ammonia provides amidine VI-3 which is used in the synthesis ofpyrimidinone VI-4 according to the methods described in the previousschemes. Subsequent treatment with CH₃SO₂Cl and triethylamine (Et₃N)results in the corresponding bicyclic intermediate VI-5. Completion ofthe synthesis can be carried out as illustrated in Scheme I.

Another method is illustrated in Scheme VII. This synthetic path beginswith an appropriately substituted ketone which can be transformed to thecorresponding nitrile intermediate VII-1. This in turn can be reactedwith 2-chloroethanol to produce compound VII-2, which can be reactedwith hydroxylamine and an acetylene dicarboxylate ester to yieldintermediate VII-4. Heating of the intermediate can yield intermediateVII-5. Synthesis of the corresponding amide derivatives can beaccomplished according to Scheme I.

In Scheme VIII, benzylation of the hydroxyl group of VII-5, as a meansof functional group protection, can be achieved using benzyl bromideunder basic conditions (for example, K₂CO₃ or NaH). Saponification ofthe ester group of VIII-1 can provide VIII-2 which can be coupled withappropriately substituted amines (R¹R²NH) using well known amide bondforming reagents, such asbenzotriazole-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP) or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU). Alternatively, the corresponding acidchloride can be formed, by treatment with oxalyl chloride, and reactedwith an appropriate amine to form the amide bond. Removal of the benzylgroup can be accomplished under a variety of conditions includingtreatment with CF₃CO₂H or H₂ (Pd—C).

In yet another method, some compounds of this invention can besynthesized according to Scheme IX. In Scheme IX, pyrimidinone IX-3, canbe produced using methods similar to those described in the previousschemes. This intermediate can be carried on to the final productaccording to a variety of paths. In one, the hydroxyl group can bebenzoylated to provide intermediate IX-4 which can be further treatedwith K₂CO₃ to effect ring closure to form the bicyclic template IX-5.Alternatively, direct treatment of IX-3 with K₂CO₃ can provideintermediate IX-6. Intermediates IX-5, an IX-6 can be used in thesynthesis the final products using the methods described in Scheme I.

In Scheme X, IX-3 can be used to synthesize the benzylated intermediateX-1. This intermediate can be carried on to final product using methodsanalogous to those described in Scheme VIII.

The synthesis of (2-(aminomethyl)-5-fluorophenyl)(morpholino)methanonehydrochloride is illustrated in Scheme XI.

In Scheme XII, bicyclic intermediate XII-1, prepared according to themethods described above, can be saponified using well known methods. Theresulting carboxylic acid, XII-3, can then be coupled to amine XII-2using standard amide bond forming reagents and methods. Removal of thebenzyl group, by hydrogenolysis or acid mediated hydrolysis provides thefinal products.

An alternative route to compounds similar to those presented in SchemeXII is given in Scheme XIII. In this scheme the ester group of XIII-1can be hydrolyzed and the resulting carboxylic acid coupled to methyl2-(aminomethyl)-5-fluorobenzoate. A second hydrolysis reaction canproduce XIII-4 which can be coupled with a second amine. This isfollowed by removal of the benzyl group to provide the final products.

In yet another method, Scheme XIV illustrates the synthesis ofsulfonamide containing examples, starting from5-fluoro-2-methylbenzen-1-sulfonlyl chloride.

Further illustration of methods used for the synthesis of certaincompounds of the invention is shown in Scheme XV. Methylation of5-(2-bromo-5-fluorophenyl)-1H-tetrazole can yield a mixture of XV-1 andXV-2 that can be separated and each of the compounds carried on to thecorresponding final products.

Some diazarine and diaziradine analogues can be synthesized according toScheme XVI.

Some examples of the invention can be synthesized according to themethods illustrated in Schemes XVII–XX.

In Scheme XXI, 2-bromo-benzonitrile or 2-bromo-4-fluoro-benzonitrile canbe coupled with an appropriate amide to provide XXI-1. Reduction of thenitrile group provides XXI-2 which can be used in the synthesis of thefinal product according to the methods described in the previousschemes. In most cases, compound XXI-1 need not be isolated but can becarried directly into the coupling reaction to form XXI-3.

The examples and methods shown in Scheme XXII are similar to thosedepicted in Scheme XXI.

Schemes XXIV and XXV further illustrate methods useful for the synthesisof some compounds of the invention.

In Scheme XXVI, intermediate XXVI-1 can be used to synthesizeintermediates XXVI-2 via palladium catalyzed coupling. Theseintermediates can be further modified to provide some of the compoundsof this invention.

Another method is illustrated in Scheme XXVII.

In Scheme XXVIII, compound XXVIII-1 can be converted to thecorresponding methylsulfonate derivate, XXVIII-2, which can besubsequently treated with sodium azide to yield XXVIII-3. This compoundin turn can serve as an intermediate for further transformation asillustrated in the scheme.

Certain examples of the current invention can be synthesized accordingto the methods illustrated in Schemes XXIX–XXXVIII.

Biological Methods

HIV-Integrase Inhibition Activity. To evaluate in-vitro activity againstHIV-integrase, 5 pmole of biotin labeled substrate DNA was bound to 100μg of Streptavidin coated PVT SPA beads (Amersham Pharmacia Biotech).Recombinant integrase (0.26 ng) was incubated with the beads for 90 minat 37° C. Unbound enzyme was removed by washing the complex followed byaddition of inhibitors and 0.1 fmol of P33 labeled target DNA. Thereaction was stopped by adding EDTA to a final concentration of 10 mM.Samples were counted in TopCountNXT (Packard) and the CPM was used as ameasure of integration. The reaction condition was as described in A.Engelman and R. Craigie, J. Virol. 69, 5908–5911 (1995). The sequencesof substrate and target DNA were described in Nucleic Acid Research22,1121–1122 (1994). Results are shown in the Table 1. Activity equal toA refers to a compound having IC₅₀=0.002 to 0.10 μM while B and C denotecompounds having IC₅₀=0.1 to 1.0 μM and IC₅₀≧1.0 μM respectively.

TABLE 1 Example Activity 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22 B 23 A 24 B 25 B 26A 27 A 28 A 29 A 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 A 38 A 39 A 40 A41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 A 54 A 55A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 C 84A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 A 96 A 97 A 98 A99 A 100 A 101 A 102 A 103 A 104 B 105 A 106 A 107 A 108 A 109 A 110 A111 A 112 A 113 A 114 A 115 A 116 A 117 A 118 A 119 A 120 A 121 A 122 A123 A 124 A 125 A 126 A 127 A 128 A 129 A 130 A 131 B 132 A 133 B 134 A135 A 136 A 137 A 138 A 139 A 140 A 141 A 142 A 143 A 144 B 145 C 146 A147 A 148 B 149 A 150 A 151 A 152 A 153 A 154 A 155 A 156 A 157 A 158 A159 B 160 A 161 A 162 A 163 A 164 A 165 A 166 B 167 A 168 A 169 A 170 A171 A 172 A 173 A 174 A 175 A 176 A 177 A 178 A 179 A 180 A 181 A 187 A188 A 189 A 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 A200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 A 211 A212 A 213 A 214 C 215 A 216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A224 A 225 A 226 A 227 A 228 A 229 A 230 A 231 A 232 A 233 A 234 A 235 A236 A 237 A 238 A 239 A 240 A 241 A 242 A 243 A 244 A 245 A 246 A 247 A248 A 249 A 250 A 251 A 252 B 253 C 254 A 255 A 256 B 257 A 258 A 259 A260 A 261 A 262 A 263 A 264 A 265 A 266 A 267 A 268 A 269 A 270 A 271 A272 A 273 A 274 A 275 A 276 A 277 A 278 A 279 A 280 A 281 A 282 A

Inhibition of HIV replication. A recombinant NL-Rluc virus wasconstructed in which a section of the nef gene from NL4-3 was replacedwith the Renilla Luciferase gene. The NL-RLuc virus was prepared byco-transfection of two plasmids, pNLRLuc and pVSVenv. The pNLRLuccontains the NL-Rluc DNA cloned into pUC18 at the PvuII site, while thepVSVenv contains the gene for VSV G protein linked to an LTR promotor.Transfections were performed at a 1:3 ratio of pNLRLuc to pVSVenv on293T cells using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad,Calif.) according to manufactures instruction, and the pseudotype virusgenerated was titered in MT-2 cells.

Susceptibility of viruses to compounds was determined by incubation inthe presence of serial dilutions of the compound. The 50% effectiveconcentration (EC₅₀) was calculated by using the exponential form of themedian effect equation where (Fa)=1/[1+(ED₅₀/drug conc.)^(m)] (Johnson VA, Byington R T. Infectivity Assay. In Techniques in HIV Research. ed.Aldovini A, Walker B D. 71–76. New York: Stockton Press. 1990). Theanti-viral activity of compounds was evaluated under three serumconditions, 10% FBS, 15 mg/ml human serum albumin/10% FBS or 40% humanserum/5% FBS, and the results from at least 2 experiments were used tocalculate the EC₅₀ values. Results are shown in the Table 2. Activityequal to A refers to a compound having EC₅₀=0.003 to 0.10 μM while B andC denote compounds with EC₅₀=0.1 to 1.0 μM and EC₅₀≧1.0 μM respectively.

TABLE 2 Example Activity 1 B 2 A 3 C 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22 B 23 A 24 C 25 C 26A 27 A 28 B 29 A 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 B 38 A 39 A 40 A41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 B 49 A 50 A 51 A 52 A 53 B 54 A 55A 56 A 57 A 58 A 59 B 60 A 61 B 62 A 63 A 64 C 65 A 66 B 67 A 68 C 69 A70 B 71 B 72 B 73 A 74 A 75 A 76 B 77 A 78 A 79 B 80 B 81 A 82 A 83 C 84A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 A 96 A 97 A 98 A99 A 100 A 101 A 102 A 103 B 104 B 105 A 106 A 107 A 108 A 109 A 110 A111 A 113 A 114 A 115 A 116 A 117 A 118 A 119 A 120 A 121 A 122 A 123 A124 A 125 A 126 A 127 A 128 A 129 A 130 A 132 A 133 B 134 A 135 A 136 A137 B 138 A 139 A 140 A 141 C 142 B 144 C 146 A 147 B 148 B 149 B 150 B151 B 152 B 153 B 154 B 155 B 156 B 157 A 158 A 159 A 160 B 161 B 162 A163 B 164 B 165 A 166 C 167 B 168 A 169 A 170 A 171 B 172 B 173 A 174 A175 B 176 A 177 A 178 A 179 B 180 C 181 A 187 B 188 B 189 A 190 A 191 B192 B 193 C 194 B 195 B 196 A 197 C 198 B 199 B 200 A 201 B 202 A 203 A204 A 205 A 206 A 207 A 208 A 209 B 210 A 211 A 212 A 213 A 214 B 215 A216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A 224 B 225 A 226 A 227 B228 B 229 A 230 A 231 A 232 A 233 A 234 A 235 A 236 B 237 A 238 A 239 A240 A 241 A 242 A 243 A 244 A 245 A 246 A 247 A 248 A 249 A 250 A 251 A252 C 253 C 254 A 255 A 256 B 257 A 258 A 259 A 260 A 262 A 263 B 265 B266 A 267 A 268 A 270 A 273 B 279 A 281 A 282 A

Additional examples are shown in Table 2a.

TABLE 2a HIV-Integrase Inhibition of HIV Example Inhibition Activityreplication 284 A A 285 NA A 286 A A 287 A A 288 A A 289 A C 290 A B 291A C 292 A C 293 A B 294 A A 295 A A 296 A A 297 A A 298 A A 299 A A 300A A 301 A A 302 A A 303 B C 304 A A 305 A A 306 A A 307 A A 308 A A 309A A 310 A A 311 A A 312 A A 313 A NA 314 A A 315 A A 316 A A 317 A A 318A A 319 A A

Combination Studies

Example 19 demonstrated synergistic or additive-synergistic HIVantiviral activity when used in conjunction with a variety of otherantiviral agents, as described below.

Virus and cell lines. The T-cell line, MT-2, was obtained through theAIDS Research and Reference Reagent Program. MT-2 cells weresub-cultured twice a week in RPMI 1640 medium supplemented with 10%fetal bovine serum, 2 mM L-glutamine, and 10 mM HEPES buffer pH 7.5. TheHIV-1 303B virus is a molecular clone derived from the NL4-3 strain ofHIV-1 that was obtained from the NIH AIDS Research and Reference ReagentProgram. For combinations with enfuvirtide, the NL36G virus was used.This NL4-3 derivative has the naturally occurring enfuvirtide resistancemutation in gp41 (36D) changed to a sensitive phenotype (D36G). Virusstocks were made by transfecting 293T cells with a proviral DNA cloneusing LipofectAMINE PLUS (Invitrogen), according to the manufacturer'sinstructions. Three days post-transfection, virus was harvested andpassaged once in MT-2 cells before titration in MT-2 cells.

Chemicals. Example 19, atazanavir, didanosine, stavudine, efavirenz, andenfuvirtide (T-20) were synthesized by Bristol-Myers Squibb usingpublished or known reactions. Amprenavir, indinavir, nelfmavir,nevirapine, lopinavir, lamivudine, ritonavir, tenofovir, saquinavir,delavirdine and abacavir were extracted from commercial formulations ofthe prescribed drugs and purified using published or common techniques.Tenofovir was tested as tenofovir disopoxil fumerate. Zidovudine andzalcitabine were purchased from Sigma, and emtricitabine from MoravekBiochemicals.

Drug Susceptibility and Cytotoxicity Assays. For drug susceptibilityassays, MT-2 cells were infected with HIV-1 303B (or NL36G), at an MOIof 0.001, and seeded into 96-well microtiter plates (2.5×10⁵ cells/ml)containing serial dilutions of test compounds. The drug combinationswere set up using ratios of the two drugs of 1:1, 1:2.5 and 2.5:1 timesthe EC₅₀ value determined for each drug in prior experiments. Each drugratio consisted of an array of 3-fold serial dilutions, and wasperformed with eight or more replicas on separate multi-well plates. HIVinfected cells were incubated at 37° C. in 5% CO₂, and on day fivepost-infection, the extent of virus replication was measured bydetermining cell viability using the CellTiter 96 AqueousNon-Radioactive Cell Proliferation Assay (Promega). Maximal cellprotection was typically seen in samples treated with the highest drugconcentration. In the cell viability assay, the tetrazolium compound MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-4-sulphophenyl-2H-tetrazolium)is added to cells, whereby enzymes in metabolically active cells convertit into a colored formazan product, which is quantitated by readingabsorbance at 490 nm. Cytotoxicity assays were performed in parallelwith the combination experiments. Here, uninfected cells were exposed tothe same drug combinations, and assayed after five days for cellviability using the MTS assay.

Analysis of Drug Combination Effects. For determination of combinationindex (CI) values, drugs were diluted in a fixed ratio and multipleratios were analyzed. The drug serial dilutions spanned a range ofconcentrations near the EC₅₀ value of each compound, so that equivalentantiviral activities could be compared. The normalized responses fromeach therapy are fit to the four-parameter logistic model with a commonminimum and maximum across all therapies. Conceptually, this equationcan be written as

${{Fa}_{i} = {A + \frac{D - A}{1 + \left( \frac{c_{1}^{I_{1}}c_{2}^{I_{2}}c_{3}^{I_{3}}c_{4}^{I_{4}}c_{5}^{I_{5}}}{{concentration}_{i}} \right)^{B_{1}^{I_{1}}B_{2}^{I_{2}}B_{3}^{I_{3}}B_{4}^{I_{4}}B_{5}^{I_{5}}}}}},{where}$$I_{j} = \left\{ {{{\begin{matrix}1 & {{{if}\mspace{14mu}{therapy}} = j} \\0 & {otherwise}\end{matrix}{for}\mspace{14mu} j} = 1},2,3,4,\mspace{14mu}{{or}\mspace{14mu} 5.}} \right.$

In this equation, Fa stands for “fraction affected,” and represents thefraction of the viral load that has been inactivated. For example, Fa of0.75 indicates that viral replication had been inhibited by 75%,relative to the no-drug controls. The EC₅₀, represented by the C_(i) inthe above equation, is the drug concentration that is expected to reducethe amount of virus by 50%, and the B_(i) are the parameters thatreflects the slope of the concentration-response curve. For this assay,A is the bottom plateau common to all curves, D is the common topplateau, B_(j) is the “slope” parameter for the jth therapy, and C^(j)is the concentration that produces an effect equal to the average of Aand D for the jth therapy. Therapies 1 and 2 correspond to monotherapies 1 and 2, respectively. Therapies 3, 4, and 5 correspond to thethree combination therapies. EC₅₀ values for each drug were determinedfrom the single drug experiments, using the above equation. The equationwas fit using a nonlinear regression routine (Proc Nlin) in PC SASversion 8.2 (SAS Institute Inc.).

To assess antiviral effects of different drug combination treatments,combination indices (CIs) were calculated according to Chou and Rideout.The combination index was computed as

${CI} = {\frac{\lbrack D\rbrack_{1}}{\lbrack{Dm}\rbrack_{1}} + \frac{\lbrack D\rbrack_{2}}{\lbrack{Dm}\rbrack_{2}}}$

In this equation [Dm]₁ and [Dm]₂ are the concentrations of drugs thatwould individually produce a specific level of effect, while [D]₁ and[D]₂ are the concentrations of drugs in combination that would producethe same level of effect.

Theoretically, additivity is implied if the CI is equal to one, synergyif the CI is less than one, and antagonism if the CI is greater thanone. However, extensive experience with combination studies indicatesthat there are inherent laboratory variables that must be taken intoaccount in interpreting the CIs. At best, a range can be constructedthat contains the likely values for the CI, given the noise in the data.In this report, these ranges are reported in parentheses next to eachpoint estimate of the CI. For example, when a CI of “0.52 (0.36, 0.69)”is reported this means that the best estimate of the CI is 0.52, but dueto noise in the data, values from 0.36 to 0.69 are also reasonablevalues for the CI. This range, 0.36 to 0.69 falls entirely below thevalue of 1.0, and hence all likely values for the CI are less than 1.0.Therefore, synergistic behavior can be inferred for this combination. Ifthe range fell entirely above 1.0, we would infer antagonistic behavior.If the range were to include 1.0, we would infer additivity.

In carrying out the combination experiments, the EC₅₀ for Example 19 andeach comparator compound was determined during the course of each study,and used in the subsequent data analysis. The determined values areconsistent with previously published data and are shown in Table 3.

TABLE 3 Anti-HIV Activity of Compounds in Two-Drug Combination StudiesHighest Drug Compound EC₅₀ (μM) Concentration (μM) Example 19 0.022 2.5Zidovudine 0.012 2.5 Didanosine 10.7 100 Stavudine 0.241 15 Lamivudine0.203 15 Abacavir 1.04 30 Tenofovir 0.018 2.5 Emtricitabine 0.053 20Zalcitabine 0.124 10 Efavirenz 0.0016 0.2 Nevirapine 0.095 5 Delavirdine0.043 5 Ritonavir 0.048 2.5 Indinavir 0.026 2.5 Nelfinavir 0.022 2.5Saquinavir 0.011 2.5 Amprenavir 0.062 2.5 Atazanavir 0.010 1 Lopinavir0.017 2.5 Enfuvirtide 0.061 2.2

Two-Drug Combinations of Example 19 with Nucleoside ReverseTranscriptase Inhibitors. Eight nucleoside RT inhibitors (didanosine,stavudine, zidovudine, lamivudine, abacavir, zalcitabine, emtricitibineand the nucleoside phosphonate, tenofovir) were combined with Example 19at a range of concentrations near the EC₅₀ value of each compound, sothat equivalent antiviral activities could be compared. All estimateswere computed using SAS Proc NLIN, and a two-parameter logistic. Data ispresented in Table 4 as the combination indices and the asymptoticconfidence intervals for RT inhibitors at different molar ratios.

Four nucleoside RT inhibitors; didanosine, stavudine, abacavir andemtricitibine, show synergistic antiviral effects in combination withExample 19 at all effective levels and all molar ratios. The other fourRT inhibitors: zidovudine, lamivudine, tenofovir and zalcitabine allhave combination indices suggestive of synergistic behavior with Example19. However, the upper ranges of the confidence intervals for some ofthe effective levels are greater than 1, so the overall effects of thesecompounds with Example 19 are classified as synergistic to additive. Nosignificant antagonism of anti-HIV activity is observed. No enhancedcytotoxicity was encountered at the highest concentrations tested withany of the drug combinations, as measured by the XTT reduction assay.

TABLE 4 Two-Drug Combinations using Example 19 and Nucleoside ReverseTranscriptase Inhibitors. Combination Indices at % HIV Inhibition^(b)Molar Ratio (Confidence Interval) (EC₅₀ Ratio)^(a) 50% 75% 90%Zidovudine   1:1 (1:1) 0.59 (0.49, 0.69) 0.56 (0.41, 0.70) 0.54 (0.36,0.70)   2:5 (1:2.5) 0.65 (0.56, 0.75) 0.73 (0.59, 0.86) 0.81 (0.57,1.06)   5:2 (2.5:1) 0.72 (0.61, 0.83) 0.83 (0.64, 1.02) 0.96 (0.63,1.30) Didanosine 1:1000 (1:1) 0.58 (0.53, 0.63) 0.47 (0.35, 0.60) 0.39(0.22, 0.56) 1:2500 (1:2.5) 0.56 (0.51, 0.62) 0.46 (0.40, 0.52) 0.38(0.32, 0.44)  1:400 (2.5:1) 0.50 (0.46, 0.54) 0.49 (0.44, 0.53) 0.48(0.42, 0.54) Stavudine   1:6 (1:1) 0.52 (0.43, 0.61) 0.46 (0.36, 0.56)0.42 (0.26, 0.57)  1:15 (1:2.5) 0.60 (0.48, 0.71) 0.60 (0.46, 0.74) 0.61(0.40, 0.83)  5:12 (2.5:1) 0.70 (0.57, 0.84) 0.63 (0.48, 0.79) 0.58(0.37, 0.81) Lamivudine   1:6 (1:1) 0.80 (0.63, 0.98) 0.80 (0.55, 1.05)0.81 (0.42, 1.21)  1:15 (1:2.5) 1.09 (0.88, 1.31) 1.00 (0.72, 1.27) 0.92(0.52, 1.33)  5:12 (2.5:1) 0.94 (0.80, 1.08) 0.84 (0.65, 1.03) 0.75(0.49, 1.02) Abacavir  1:30 (1:1) 0.68 (0.59, 0.76) 0.67 (0.56, 0.79)0.67 (0.49, 0.84)  1:75 (1:2.5) 0.87 (0.77, 0.97) 0.74 (0.63, 0.85) 0.63(0.50, 0.77)  1:12 (2.5:1) 0.86 (0.76, 0.96) 0.82 (0.68, 0.96) 0.79(0.58, 0.99) Tenofovir   1:1 (1:1) 0.66 (0.57, 0.75) 0.54 (0.45, 0.62)0.43 (0.33, 0.53)   2:5 (1:2.5) 0.68 (0.59, 0.77) 0.60 (0.48, 0.72) 0.52(0.36, 0.69)   5:2 (2.5:1) 0.90 (0.77, 1.04) 0.84 (0.67, 1.01) 0.79(0.55, 1.03) Zalcitabine   1:4 (1:1) 0.61 (0.48, 0.73) 0.56 (0.39, 0.73)0.53 (0.28, 0.79)  1:10 (1:2.5) 0.55 (0.44, 0.66) 0.40 (0.31, 0.49) 0.30(0.18, 0.42)   5:8 (2.5:1) 0.80 (0.62, 0.97) 0.82 (0.58, 1.07) 0.86(0.46, 1.26) Emtricitabine   1:8 (1:1) 0.31 (0.27, 0.36) 0.23 (0.18,0.28) 0.18 (0.12, 0.24)  1:20 (1:2.5) 0.31 (0.26, 0.37) 0.23 (0.19,0.29) 0.17 (0.12, 0.28)  5:16 (2.5:1) 0.33 (0.28, 0.38) 0.25 (0.20,0.30) 0.19 (0.13, 0.25) ^(a)Ratio of Example 19 to comparator compound^(b)A lower bound of the asymptotic confidence interval greater than 1indicates antagonisms, an upper bound of less than 1 indicates synergismand a value of 1 being contained in the interval indicates additivity.The 95% confidence intervals are shown in parenthesis, and represent ameasure of variability in the data.

Two-Drug Combinations of Example 19 with Non-Nucleoside ReverseTranscriptase Inhibitors. Three non-nucleoside RT inhibitors werecombined with Example 19 at a range of concentrations near the EC₅₀value of each compound, as described above for nucleoside RT inhibitors.Data is presented in Table 5 as the combination indices and theasymptotic confidence intervals at different molar ratios. Of the three,nevaripine shows strong synergistic effects in combination with Example19. Synergy is seen at all effective concentrations and at all molarratios. Sustiva and nevirapine also exhibit combination indicesindicative of synergism at most effective concentrations and molarratios. However, in some cases, the upper range of the asymptoticconfidence interval is greater than 1, so an additive effect can not beruled out. No enhanced cytotoxicity was observed at the highestconcentrations tested with any of the drug combinations, suggesting apotential for therapeutic efficacy of Example 19 combinations withnon-nucleoside RT inhibitors.

TABLE 5 Two-Drug Combinations using Example 19 and Non-NucleosideReverse Transcriptase Inhibitors. Combination Indices at % HIVInhibition^(b) Molar Ratio (Confidence Interval) (EC₅₀ Ratio)^(a) 50%75% 90% Efavirenz  5:2 (1:1) 0.83 (0.75, 0.92) 0.76 (0.64, 0.88) 0.70(0.54, 0.85)  1:1 (1:2.5) 0.95 (0.86, 1.04) 0.93 (0.85, 1.02) 0.93(0.79, 1.06) 25:4 (2.5:1) 1.01 (0.92, 1.10) 0.96 (0.83, 1.10) 0.94(0.73, 1.14) Nevirapine  1:2 (1:1) 0.72 (0.62, 0.82) 0.69 (0.55, 0.83)0.66 (0.46, 0.87)  1:5 (1:2.5) 0.76 (0.64, 0.87) 0.81 (0.64, 0.97) 0.87(0.59, 1.15)  5:4 (2.5:1) 0.73 (0.62, 0.83) 0.68 (0.55, 0.81) 0.64(0.45, 0.84) Delavirdine  1:2 (1:1) 0.76 (0.64, 0.89) 0.60 (0.47, 0.74)0.48 (0.31, 0.64)  1:5 (1:2.5) 0.68 (0.58, 0.77) 0.44 (0.32, 0.54) 0.28(0.17, 0.39)  5:4 (2.5:1) 0.80 (0.68, 0.92) 0.53 (0.42, 0.63) 0.35(0.25, 0.45) ^(a)Ratio of Example 19 to comparator compound. ^(b)A lowerbound of the asymptotic confidence interval greater than 1 indicatesantagonisms, an upper bound of less than 1 indicates synergism, and avalue of 1 being contained in the interval indicates additivity. The 95%confidence intervals are shown in parenthesis, and represent a measureof variability in the data.

Two-Drug Combinations Involving Example 19 and HIV Protease Inhibitors.Evaluation of Example 19 for drug combination therapy with proteaseinhibitors was carried out using indinavir, amprenavir, nelfmavir,lopinavir, saquinavir, ritonavir and atazanavir. Results from thistwo-drug combination study are summarized in Table 6. Again, thecombination indices observed with Example 19 and all protease inhibitorsat almost all effective levels and molar ratios are suggestive of asynergistic relationship. This is especially true for saquinavir andatazanavir, where the confidence interval is below one at allconcentrations and effective levels. Meanwhile, the upper range of theconfidence interval is greater than one in only one condition forritonavir, indinavir and lopinavir, so an additive relationship withExample 19 cannot be ruled out. In addition, the upper range of theconfidence interval for nelfmavir and amprenavir are slightly greaterthan 1 under a few conditions, suggestive of a synergistic-additiveeffect for these compounds with Example 19. No cytotoxicity was observedat the highest concentrations used in any of these combination antiviralassays.

TABLE 6 Two-Drug Combination using Example 19 and Protease Inhibitors.Combination Indices at % HIV Inhibition^(b) Molar Ratio (ConfidenceInterval) (EC₅₀ Ratio)^(a) 50% 75% 90% Indinavir  1:1 (1:1) 0.86 (0.80,0.92) 0.71 (0.62, 0.81) 0.60 (0.46, 0.73)  2:5 (1:2.5) 0.92 (0.84, 0.99)0.84 (0.76, 0.92) 0.77 (0.66, 0.89)  5:2 (2.5:1) 0.94 (0.87, 1.02) 0.79(0.71, 0.87) 0.67 (0.57, 0.77) Nelfinavir  1:1 (1:1) 0.79 (0.73, 0.86)0.75 (0.67, 0.82) 0.71 (0.56, 0.84)  2:5 (1:2.5) 0.97 (0.89, 1.06) 0.87(0.79, 0.95) 0.78 (0.68, 0.88)  5:2 (2.5:1) 1.09 (1.00, 1.18) 0.98(0.89, 1.08) 0.90 (0.76, 1.03) Saquinavir  1:1 (1:1) 0.77 (0.70, 0.84)0.67 (0.58, 0.75) 0.58 (0.47, 0.69)  2:5 (1:2.5) 0.43 (0.38, 0.48) 0.51(0.42, 0.59) 0.59 (0.44, 0.74)  5:2 (2.5:1) 0.81 (0.72, 0.89) 0.77(0.66, 0.89) 0.74 (0.57, 0.91) Amprenavir  1:1 (1:1) 0.83 (0.67, 1.00)0.84 (0.61, 1.08) 0.89 (0.50, 1.23)  2:5 (1:2.5) 0.84 (0.69, 0.99) 0.77(0.58, 0.96) 0.75 (0.46, 1.04)  5:2 (2.5:1) 0.90 (0.77, 1.04) 0.62(0.50, 0.74) 0.44 (0.30, 0.57) Atazanavir  5:2 (1:1) 0.87 (0.79, 0.96)0.67 (0.55, 0.80) 0.52 (0.37, 0.67)  1:1 (1:2.5) 0.65 (0.51, 0.78) 0.45(0.31, 0.58) 0.31 (0.19, 0.44) 25:4 (2.5:1) 0.78 (0.69, 0.86) 0.60(0.54, 0.67) 0.47 (0.40, 0.54) Lopinavir  1:1 (1:1) 0.74 (0.67, 0.82)0.77 (0.66, 0.88) 0.84 (0.65, 1.02)  2:5 (1:2.5) 0.77 (0.66, 0.88) 0.56(0.36, 0.75) 0.41 (0.19, 0.64)  5:2 (2.5:1) 0.76 (0.69, 0.83) 0.62(0.55, 0.70) 0.54 (0.47, 0.61) Ritonavir  1:1 (1:1) 0.80 (0.67, 0.93)0.57 (0.41, 0.73) 0.44 (0.23, 0.65)  2:5 (1:2.5) 0.73 (0.59, 0.88) 0.64(0.48, 0.80) 0.61 (0.38, 0.85)  5:2 (2.5:1) 0.92 (0.72, 1.11) 0.72(0.50, 0.93) 0.59 (0.32, 0.87) ^(a)Ratio of Example 19 to comparatorcompound. ^(b)A lower bound of the asymptotic confidence intervalgreater than 1 indicates antagonisms, an upper bound of less than 1indicates synergism, and a value of 1 being contained in the intervalindicates additivity. The 95% confidence intervals are shown inparenthesis, and represent a measure of variability in the data.

Two-Drug Combination of Example 19 with Enfuvirtide. Enfuvirtide (T-20)is an HIV gp41 fusion inhibitor and the first approved entry classinhibitor. The results presented in Table 7 indicate that thecombination of Example 19 with T-20 is synergistic. No significantcytotoxicity was observed at the highest concentration of the combineddrugs.

TABLE 7 Two-Drug Combination study of Example 19 with Enfuvirtide. MolarRatio Combination Indices at % HIV Inhibition^(b) (EC₅₀ Ratio)^(a)(Confidence Interval) Enfuvirtide 50% 75% 90%  5:44 (1:1) 0.68 (0.59,0.77) 0.59 (0.48, 0.70) 0.52 (0.37, 0.67)  1:22 (1:2.5) 0.75 (0.65,0.85) 0.60 (0.49, 0.70) 0.48 (0.34, 0.61) 25:88 (2.5:1) 0.76 (0.65,0.86) 0.73 (0.59, 0.86) 0.71 (0.50, 0.92) ^(a)Ratio of Example 19 tocomparator compound. ^(b)A lower bound of the asymptotic confidenceinterval greater than 1 indicates antagonisms, an upper bound of lessthan 1 indicates synergism, and a value of 1 being contained in theinterval indicates additivity. The 95% confidence intervals are shown inparenthesis, and represent a measure of variability in the data.

Pharmaceutical Composition and Methods of Use

The compounds of this invention inhibit HIV integrase. HIV integraseinhibitors belonging to a class of diketo acid compounds prevented viralintegration and inhibited HIV-1 replication in cells (Hazuda et al.Science 2000, 287, 646). Recently, HIV integrase inhibitors have beenaccepted into clinical trials for treating AIDS and HIV infection(Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke DrugsFut. 2002, 27, 1101).

Accordingly, another aspect of the invention is a method for treatingHIV infection in a human patient comprising administering atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, with apharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating HIV infectionin a human patient comprising the administration of a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, with a therapeutically effectiveamount of at least one other agent used for treatment of AIDS or HIVinfection selected from the group consisting of nucleoside HIV reversetranscriptase inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIVattachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding ormaturation inhibitors, and HIV integrase inhibitors.

Another aspect of the invention is a method wherein the agent is anucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the nucleoside HIVreverse transcriptase inhibitor is selected from the group consisting ofabacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir,zalcitabine, and zidovudine, or a pharmaceutically acceptable salt orsolvate thereof.

Another aspect of the invention is a method wherein the agent is anon-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the non-nucleosideHIV reverse transcriptase inhibitor is selected from the groupconsisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVprotease inhibitor.

Another aspect of the invention is a method wherein the HIV proteaseinhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfmavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVfusion inhibitor.

Another aspect of the invention is a method wherein the HIV fusioninhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptablesalt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVattachment inhibitor.

Another aspect of the invention is a method wherein the agent is a CCR5inhibitor.

Another aspect of the invention is a method wherein the CCR5 inhibitoris selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140,and UK-427,857, or a pharmaceutically acceptable salt or solvatethereof.

Another aspect of the invention is a method wherein the agent is a CXCR4inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitoris AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVbudding or maturation inhibitor.

Another aspect of the invention is a method wherein the budding ormaturation inhibitor is PA-457, or a pharmaceutically acceptable salt,or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVintegrase inhibitor.

Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt or solvate thereof, with atleast one other agent used for treatment of AIDS or HIV infectionselected from the group consisting of nucleoside HIV reversetranscriptase inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIVattachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding ormaturation inhibitors, and HIV integrase inhibitors, and apharmaceutically acceptable carrier.

Another aspect of the invention is the composition wherein the agent isa nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is the composition wherein thenucleoside HIV transcriptase inhibitor is selected from the groupconsisting of abacavir, didanosine, emtricitabine, lamivudine,stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceuticallyacceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isa non-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is the composition wherein thenon-nucleoside HIV reverse transcriptase inhibitor is selected from thegroup consisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV protease inhibitor.

Another aspect of the invention is the composition wherein the HIVprotease inhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfmavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV fusion inhibitor.

Another aspect of the invention is the composition method wherein theHIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceuticallyacceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV attachment inhibitor.

Another aspect of the invention is the composition wherein the agent isa CCR5 inhibitor.

Another aspect of the invention is the composition wherein the CCR5inhibitor is selected from the group consisting of Sch-C, Sch-D,TAK-220, PRO-140, and UK-427,857, or a pharmaceutically acceptable saltor solvate thereof.

Another aspect of the invention is a method wherein the agent is a CXCR4inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitoris AMD-3100 or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV budding or maturation inhibitor.

Another aspect of the invention is the composition wherein the buddingor maturation inhibitor is PA-457, or a pharmaceutically acceptable saltor solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV integrase inhibitor.

“Combination,” “coadministration,” “concurrent,” and similar termsreferring to the administration of a compound of Formula I with at leastone anti-HIV agent mean that the components are part of a combinationantiretroviral therapy or highly active antiretroviral therapy (HAART)as understood by practitioners in the field of AIDS and HIV infection.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of AIDS and HIV infection. In general, the goals of treatmentare suppression of viral load, restoration and preservation ofimmunologic function, improved quality of life, and reduction ofHIV-related morbidity and mortality.

“Patient” means a person infected with the HIV virus and suitable fortherapy as understood by practitioners in the field of AIDS and HIVinfection.

“Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” andrelated terms are used as understood by practitioners in the field ofAIDS and HIV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of Formula I or its pharmaceutically acceptable salt and apharmaceutically acceptable carrier and may contain conventionalexcipients. A therapeutically effective amount is that which is neededto provide a meaningful patient benefit. Pharmaceutically acceptablecarriers are those conventionally known carriers having acceptablesafety profiles. Compositions encompass all common solid and liquidforms including capsules, tablets, losenges, and powders as well asliquid suspensions, syrups, elixers, and solutions. Compositions aremade using common formulation techniques, and conventional excipients(such as binding and wetting agents) and vehicles (such as water andalcohols) are generally used for compositions.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agentswill be present in a unit range similar to agents of that class usedclinically. Typically, this is 0.25–1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1–100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other antiretroviral agents will be present in a unitrange similar to agents of that class used clinically. Typically, thisis 1–100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other antiretroviral agents used clinically. Typically,the daily dose will be 1–100 mg/kg body weight daily. Generally, morecompound is required orally and less parenterally. The specific dosingregime, however, will be determined by a physician using sound medicaljudgement.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating AIDS and HIVinfection. Some of these agents include HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integraseinhibitors, HIV nucleoside reverse transcriptase inhibitors, HIVnon-nucleoside reverse transcriptase inhibitors, HIV proteaseinhibitors, budding and maturation inhibitors, immunomodulators, andanti-infectives. In these combination methods, the compound of Formula Iwill generally be given in a daily dose of 1–100 mg/kg body weight dailyin conjunction with other agents. The other agents generally will begiven in the amounts used therapeutically. The specific dosing regime,however, will be determined by a physician using sound medicaljudgement.

Table 8 lists some agents useful in treating AIDS and HIV infectionwhich are suitable for this invention.

TABLE 8 DRUG NAME MANUFACTURER INDICATION ANTIVIRALS 097 Hoechst/BayerHIV infection, AIDS, (non-nucleoside reverse ARC transcriptaseinhibitor) Amprenavir Glaxo Wellcome HIV infection, AIDS, 141 W94 ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, AIDS, GW 1592 ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC,in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection, ARC, AL-721 Ethigen PGL HIV positive,(Los Angeles, CA) AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcomaHIV in combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-MyersSquibb/ HIV infection, AIDS, (CGP-73547) Novartis ARC (proteaseinhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, AIDS,(CGP-61755) Novartis ARC (protease inhibitor) CI-1012 Warner-LambertHIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes,papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral, CMV retinitis DelaviridinePharmacia-Upjohn HIV infection, AIDS, (RT inhibitor) ARC Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomaticJapan) ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, AIDS, (proteaseinhibitor) (Camden, NJ) ARC Efavirenz DuPont Merck HIV infection, AIDS,(DMP 266) ARC (−)6-Chloro-4-(S)- cyclopropylethynyl- 4(S)-trifluoro-methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE (non-nucleosideRT inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA)Famciclovir Smith Kline herpes zoster, herpes simplex FTC EmoryUniversity HIV infection, AIDS, (reverse transcriptase ARC inhibitor) GS840 Gilead HIV infection, AIDS, (reverse transcriptase ARC inhibitor)HBY097 Hoechst Marion HIV infection, AIDS, (non-nucleoside reverseRoussel ARC transcriptaseinhibitor) Hypericin VIMRx Pharm. HIVinfection, AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi'sInterferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 InterferonSciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC,asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer InstituteHIV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection,AIDS, (reverse transcriptase ARC, also with AZT inhibitor) LobucavirBristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,AIDS, (protease inhibitor) Pharmaceuticals ARC Nevirapine BoeheringerHIV infection, AIDS, (RT inhibitor) Ingleheim ARC Novapren NovaferonLabs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDSOctapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis,HIV Phosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, (protease inhibitor)ARC Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, AIDS, Tech (Houston, TX) ARC Ritonavir Abbott HIV infection,AIDS, (protease inhibitor) ARC Saquinavir Hoffmann- HIV infection, AIDS,(protease inhibitor) LaRoche ARC Stavudine; d4T Bristol-Myers Squibb HIVinfection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir GlaxoWellcome Genital HSV & CMVinfections Virazole Viratek/ICN asymptomaticHIV- Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIVinfection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC,Kaposi's sarcoma, in combination with other therapies Tenofovirdisoproxil, Gilead HIV infection, AIDS fumarate salt (Viread ®) (reversetranscriptase inhibitor) Combivir ® GSK HIV infection, AIDS (reversetranscriptase inhibitor) abacavir succinate GSK HIV infection, AIDS (orZiagen ®) (reverse transcriptase inhibitor) Reyataz ® Bristol-MyersSquibb HIV infection, AIDS (atazanavir) Fuzeon Roche/Trimeris HIVinfection, AIDS, (Enfuvirtide, T-20) viral fusion inhibitor Trizivir ®HIV infection, AIDS Kaletra ® Abbott HIV infection, AIDS, ARCIMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia UpjohnAdvanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharmBlocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, incombination w/TNF (tumor necrosis factor) Granulocyte Genetics InstituteAIDS Macrophage Colony Sandoz Stimulating Factor GranulocyteHoechst-Roussel AIDS Macrophage Colony Immunex Stimulating FactorGranulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZTStimulating Factor HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcomaMuramyl-Tripeptide Amgen AIDS, in Granulocyte combination w/AZT ColonyStimulating Factor Remune Immune Response Immunotherapeutic Corp. rCD4Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARChybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma, Alfa 2a in combination w/AZT AIDS,ARC SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of oral Nystatin Pastille candidiasis Ornidyl MerrellDow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM& IV) (Rosemont, IL) Trimethoprim Antibacterial Trimethoprim/sulfaAntibacterial Piritrexim Burroughs Wellcome PCP treatment PentamidineFisons Corporation PCP prophylaxis Isethionate for Inhalation SpiramycinRhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm.Histoplasmosis; R51211 cryptococcal meningitis TrimetrexateWarner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcomaRecombinant Human Ortho Pharm. Corp. Severe anemia assoc. Erythropoietinwith AZT therapy Recombinant Human Serono AIDS-related wasting, GrowthHormone cachexia Megestrol Acetate Bristol-Myers Squibb Treatment ofanorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and NutritionPharmaceuticals malabsorption related to AIDS

DESCRIPTION OF SPECIFIC EMBODIMENTS

2-(2-(Methylthio)ethoxy)acetic acid. A solution of 2-methylthioethanol(10.0 g, 0.108 mol) in dry tetrahydrofuran (25 ml) was added dropwise,over 30 min, to a suspension of sodium hydride (9.54 g of a 60%dispersion in mineral oil, 0.238 mol, washed twice with hexane) in drytetrahydrofuran (250 ml) at 22° C. After 30 min, a solution ofchloroacetic acid (110.25 g, 0.108 mol) in dry tetrahydrofuran (20 ml)was added dropwise, over 30 min at 22° C., and the resulting mixture wasthen heated under reflux for 5 h. The cooled mixture was treated with250 ml of 1 N hydrochloric acid and sodium chloride added to the aqueousphase until saturation. The organic phase was separated and the aqueousphase washed with ethyl acetate. The combined organic extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Distillation of the resultingresidue in vacuo gave 11.27 g (69% yield) of the title acid as a clearoil; bp 85–95° C./0.3 torr (bulb to bulb distillation, air bathtemperature). ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.18 (3H, s, SCH₃), 2.76 (2H,t, J=6.6 Hz, CH₂), 3.77 (2H, t, J=6.6 Hz, CH₂), 4.20 (2H, s, OCH₂).

Methyl 2-(2-(methylthio)ethoxy)acetate. A solution of intermediate 1,2-(2-(methylthio)ethoxy)acetic, (11.27 g, 0.075 mol) in drydichloromethane (50 ml) was treated with oxalylchloride (13.0 ml, 0.15mol) followed by a drop of N,N-dimethylformamide and the resultingmixture stirred at 22° C. for 5 h. The solvent and excess reagent werethen evaporated under reduced pressure and the residual acid chloridewas added dropwise to a cold mixture (0–5° C.) of methanol (30 ml) andpyridine (10 ml) in dichloromethane (50 ml). After 1 h at 22° C., thesolvent was evaporated under reduced pressure. The resulting residue wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid, saturatedsodium bicarbonate and brine, dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. Distillation of the resultingresidue in vacuo gave 11.42 g (93% yield) of the title ester as a clearoil; bp 65–75° C./0.1 torr (bulb to bulb distillation, air bathtemperature). ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.17 (3H, s, SCH₃), 2.75 (2H,t, J=6.9 Hz, CH₂), 3.74 (2H, t, J=6.9 Hz, CH₂), 3.77 (3H, s, OCH₃), 4.15(2H, s, OCH₂).

2-(2-(Methylthio)ethoxy)acetamidine hydrochloride salt. Intermediate 2,methyl 2-(2-(methylthio)ethoxy)acetate, (4.69 g, 28.6 mmol) was added toa solution of methylchloroaluminum amide (H. Geilen, C. Alonso-Alija, M.Hendrix, U. Niewohner and D. Schauss, Tetrahedron Lett., 2002, 43,419–421)(0.114 mol; prepared in toluene (50 ml) from ammonium chloride6.30 g (0.117 mol) and 57.0 ml (0.114 mol) of a 2 M solution oftrimethylaluminum in toluene) and the resulting mixture was heated at80° C. for 18 h. The reaction mixture was then cooled to 0° C., treateddropwise with methanol (100 ml) and stirred for another hour at 25° C.The solid which was formed was filtered and washed with methanol (300ml). The combined filtrate was concentrated to give a white paste whichwas diluted with isopropanol (160 ml) and acetone (40 ml) and stirred at25° C. for 1 h. The solid was then filtered off and the filtrateconcentrated in vacuo to give 3.50 g (62% yield) of the title compoundas an oil. ¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.10 (3H, s, SCH₃), 2.71 (2H,t, J=6.8 Hz, CH₂), 3.66 (2H, t, J=6.8 Hz, CH₂), 4.34 (2H, s, OCH₂). MS(ESI⁺) m/z 149 [M+H⁺].

Ethyl5-benzyloxy-2-{(2-(methylthio)ethoxy)methyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylate.Diethyl oxalate (2.77 g, 19.0 mmol) and ethyl benzyloxyacetate (3.69 g,19.0 mmol) in dry tetrahydrofuran (30 ml) were treated at 22° C. withsodium hydride (0.83 g of a 60% dispersion in mineral oil, 20.9 mmol)followed by ethanol (10 μl) and the resulting mixture was stirred at 22°C. for 18 h. The tetrahydrofuran was evaporated under reduced pressureto give an orange syrup. A mixture of intermediate 3,2-(2-(methylthio)ethoxy)acetamidine hydrochloride salt, (3.50 g, 19.0mmol) in a solution of sodium ethoxide (9.5 mmol, prepared from 0.22 gof sodium in ethanol 25 ml) was then added all at once to the aboveadduct and the resulting mixture heated at 60° C. for 3 h. Acetic acid(2 ml) was added and the ethanol was evaporated under reduced pressure.The residue was diluted with ethyl acetate washed successively withsaturated sodium bicarbonate and brine, then dried over anhydrousmagnesium sulfate and concentrated under reduced pressure.Chromatography on silica gel (elution with a gradient of ethyl acetate20–30% in toluene) gave 0.728 g (10% yield) of the title ester as aclear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH₃),2.18 (3H, s, SCH₃), 2.78 (2H, t, J=6.0 Hz, CH₂), 3.78 (2H, t, J=6.0 Hz,CH₂), 4.36 (2H, q, J=7.1 Hz, OCH₂), 4.54 (2H, s, OCH₂), 5.35 (2H, s,OCH₂), 7.37 (3H, m, aromatics), 7.48 (2H, m, aromatics). HRMS (ESI⁺)calculated for C₁₈H₂₃N₂O₅S [M+H⁺]: 379.1328. found: 379.1314.

Ethyl5-benzyloxy-2-{(2-(dimethylsulfonium)ethoxy)methyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylateiodide. A solution of intermediate 4, ethyl5-benzyloxy-2-{(2-(methylthio)ethoxy)methyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(0.555 g, 1.47 mmol) in dichloromethane (10 ml) was treated at 22° C.with iodomethane (2.0 ml, 21.5 mmol) for 10 days. Evaporation of thesolvent and excess reagent gave the title compound (0.76 g) as an oilwhich was used without further purification. ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.32 (3H, t, J=7.1 Hz, CH₃), 3.26 (6H, s, SCH₃), 4.02 (2H, m,CH₂), 4.23 (2H, m, CH₂), 4.34 (2H, q, J=7.1 Hz, OCH₂), 4.69 (2H, s,OCH₂), 5.23 (2H, s, OCH₂), 7.35–7.5 (5H, m, aromatics). MS (ESI⁺) m/z393 [M⁺].

Ethyl3-benzyloxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of intermediate 5, ethyl5-benzyloxy-2-{(2-(dimethylsulfonium)ethoxy)methyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylateiodide, (0.76 g, 1.47 mmol) in dry N,N-dimethylformamide (10 ml) wastreated at 22° C. with powdered anhydrous potassium carbonate (2.5 g)and the resulting mixture stirred for 48 h. The solid was then filteredand the filtrate evaporated in vacuo. The residue was diluted with ethylacetate washed successively with 0.1 N hydrochloric acid, saturatedsodium bicarbonate, brine and dried over anhydrous magnesium sulfate.Evaporation of the solvent followed by chromatography on silica gel(elution with a gradient of ethyl acetate 20–50% in toluene) gave 0.347g (72% yield) of the title ester as white prisms; mp 103–104° C. (ethylacetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.34 (3H, t, J=7.1 Hz,CH₃), 4.03 (2H, t, J=5.6 Hz, CH₂), 4.11 (2H, t, J=5.6 Hz, CH₂), 4.37(2H, q, J=7.1 Hz, OCH₂), 4.74 (2H, s, OCH₂), 5.30 (2H, s, OCH₂), 7.38(3H, m, aromatics), 7.50 (2H, m, aromatics). Anal. Calcd for C₁₇H₁₈N₂O₅:C, 61.81; H, 5.49; N, 8.48. Found: C, 61.55; H, 5.53; N, 8.39.

3-(Benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid. A solution of intermediate 6, ethyl3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(0.300 g, 0.91 mmol) in ethanol (10 ml) was treated with 3 ml (3.0 mmol)of 1 N sodium hydroxide and stirred at 25° C. for 30 min. The solutionwas then acidified with 1 N hydrochloric acid, extracted with ethylacetate, washed with brine and dried over anhydrous magnesium sulfate.Evaporation of the solvent gave 0.264 g (96% yield) of the title acid aswhite crystals; mp 171° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 4.03 (2H, t, J=5.3 Hz, CH₂), 4.12 (2H, t, J=5.3 Hz, CH₂), 4.73(2H, s, OCH₂), 5.53 (2H, s, OCH₂), 7.35–7.42 (3H, m, aromatics), 7.53(2H, m, aromatics). Anal. Calcd for C₁₅H₁₄N₂O₅: C, 59.60; H, 4.67; N,9.27. Found: C, 59.35; H, 4.69; N, 9.10.

Ethyl3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of intermediate 6, ethyl3-benzyloxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.236 g, 0.714 mmol) in a mixture of ethyl acetate (60 ml) and ethanol(20 ml) was treated with 1 atm of hydrogen at 25° C. over 10% palladiumon activated carbon (0.10 g) for 2.5 h to give 0.160 g (94% yield) ofthe title compound as white needles; mp 172–174° C. (ethyl acetate).¹HNMR 400 MHz (CDCl₃) δ ppm: 1.47 (3H, t, J=7.3 Hz, CH₃), 4.08 (4H, m,2×CH₂), 4.54 (2H, q, J=7.3 Hz, OCH₂), 4.72 (2H, s, OCH₂), 10.75 (1H, s,OH). Anal. Calcd for C₁₀H₁₂N₂O₅: C, 50.00; H, 5.03; N, 11.66. Found: C,50.01; H, 4.95; N, 11.54.

2-(2-(Methylthio)ethoxy)propanoic acid. Addition of 2-methylthioethanol(10.0 g, 0.108 mol) to sodium hydride (9.54 g of a 60% dispersion inmineral oil, 0.238 mol, washed twice with hexane) followed by reactionwith 2-bromopropionic acid (16.6 g, 0.108 mol) gave 13.81 g (78% yield)of the title compound as a clear oil; bp 80–90° C./0.2 torr (bulb tobulb distillation, air bath temperature). ¹HNMR 400 MHz (CDCl₃) δ ppm:1.49 (3H, d, J=7.0 Hz, CH₃), 2.18 (3H, s, SCH₃), 2.76 (2H, t, J=6.6 Hz,CH₂), 3.74 (2H, t, J=6.6 Hz, CH₂), 4.07 (1H, d, J=7.0 Hz, OCH).

Methyl 2-(2-(methylthio)ethoxy)propanoate. Reaction of intermediate 9,2-(2-(methylthio)ethoxy)propanoic acid, (13.70 g, 0.083 mol) with oxalylchloride followed by reaction with methanol gave 14.27 g (96% yield) ofthe title ester as a clear oil; bp 55–60° C./0.3 torr (bulb to bulbdistillation, air bath temperature). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.42(3H, d, J=7.0 Hz, CH₃), 2.15 (3H, s, SCH₃), 2.71 (2H, t, J=6.8 Hz, CH₂),3.56 (1H, m, CH), 3.75 (3H, s, OCH₃), 3.78 (1H, m, CH), 4.15 (1H, q,J=7.0 Hz, OCH).

2-(2-(Methylthio)ethoxy)propanamidine hydrochloride salt. Intermediate10, methyl 2-(2-(methylthio)ethoxy)propanoate, (10.00 g, 56.1 mmol) wasadded to a solution of methylchloroaluminum amide (0.224 mol; preparedin toluene (100 ml) from ammonium chloride 12.36 g (0.231 mol) and 112.0ml (0.224 mol) of a 2 M solution of trimethylaluminum in toluene} asdescribed in the preparation of intermediate 3 to give 7.70 g (69%yield) of the title compound as an oil. ¹HNMR 400 MHz (D₂O) δ ppm: 1.37(3H, d, J=6.6 Hz, CH₃), 2.01 (3H, s, SCH₃), 2.65 (2H, t, J=5.6 Hz, CH₂),3.64 (2H, m, CH₂), 4.30 (1H, q, J=6.6 Hz, OCH). MS (ESI⁺) m/z 163[M+H⁺].

Ethyl5-benzyloxy-2-{1-(2-(methylthio)ethoxy)ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylate.Diethyl oxalate (5.66 g, 38.7 mmol) and ethyl benzyloxyacetate (7.52 g,38.7 mmol) in dry tetrahydrofuran (60 ml) were treated at 22° C. withsodium hydride (1.70 g of a 60% dispersion in mineral oil, 42.5 mmol)and the condensation product was reacted with a mixture of intermediate11, 2-(2-(methylthio)ethoxy)propanamidine hydrochloride salt, (7.70 g,38.7 mmol) in a solution of sodium ethoxide (19.3 mmol, prepared from0.445 g of sodium) in ethanol (50 ml) to give 2.29 g (15% yield) of thetitle ester as a clear oil after chromatography on silica gel. ¹HNMR 400MHz (CDCl₃) δ ppm: 1.33 (3H, t, J=7.1 Hz, CH₃), 1.54 (3H, d, J=7.1 Hz,CH₃), 2.16 (3H, s, SCH₃), 2.7–2.8 (2H, m, CH₂), 3.54 (1H, m, CH), 3.86(1H, m, CH), 4.37 (2H, q, J=7.1 Hz, OCH₂), 4.47 (1H, q, J=7.1 Hz, OCH),5.34 (2H, ABq, J_(AB)=11.0 Hz, OCH₂), 7.37 (3H, m, aromatics), 7.49 (2H,m, aromatics). MS (ESI⁺) m/z 393 [M+H⁺].

Ethyl5-benzyloxy-2-{1-(2-(dimethylsulfonium)ethoxy)ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylateiodide. A solution of intermediate 12, ethyl5-benzyloxy-2-{1-(2-(methylthio)ethoxy)ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(1.63 g, 4.15 mmol) in dichloromethane (5 ml) was treated at 22° C. withiodomethane (5.0 ml, 53.9 mmol) for 5 days as described for thepreparation of intermediate 5, to give the title compound (2.22 g) as anoil which was used without further purification. ¹HNMR 400 MHz (CDCl₃) δppm: 1.32 (3H, t, J=7.1 Hz, CH₃), 1.66 (3H, d, J=6.6 Hz, CH₃), 3.15 (3H,s, SCH₃), 3.32 (3H, s, SCH₃), 3.4 (1H, m, CH), 4.01 (2H, m, CH₂), 4.37(2H, q, J=7.1 Hz, OCH₂), 4.45 (1H, m, CH), 4.63 (1H, q, J=6.6 Hz, OCH),5.28 (2H, OCH₂), 7.38 (3H, m, aromatics), 7.50 (2H, m, aromatics). MS(ESI⁺) m/z 407 [M⁺].

Ethyl3-(benzyloxy)-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of intermediate 13, ethyl5-benzyloxy-2-{1-(2-(dimethylsulfonium)ethoxy)ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylateiodide (2.22 g, 4.15 mmol) in dry N,N-dimethylformamide (30 ml) wastreated at 22° C. with powdered anhydrous potassium carbonate (6 g) andstirred for 40 h. The solid was then filtered and the filtrate wasconcentrated in vacuo. The residue was diluted with ethyl acetate,washed with 0.1 N hydrochloric acid, saturated sodium bicarbonate andbrine then dried over anhydrous magnesium sulfate. Evaporation of thesolvent and chromatography of the residue on silica gel (elutiontoluene-ethyl acetate 7:3) gave 1.0 g (70% yield) of the title ester aswhite crystals; mp 48–50° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH₃), 1.68 (3H, d, J=6.6 Hz,CH₃), 3.91 (2H, m, CH₂), 4.17–4.31 (2H, m, CH₂), 4.37 (2H, q, J=7.1 Hz,OCH₂), 4.73 (1H, q, J=6.6 Hz, OCH), 5.30 (2H, ABq, J_(AB)=11.0 Hz,OCH₂), 7.38 (3H, m, aromatics), 7.50 (2H, m, aromatics). Anal. Calcd forC₁₈H₂₀N₂O₅: C, 62.78; H, 5.85; N, 8.13. Found: C, 62.69; H, 6.01; N,8.16.

Ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.Hydrogenolysis of intermediate 14, ethyl3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.610 g, 1.77 mmol) in a mixture of ethyl acetate (75 ml) and ethanol(75 ml) at 25° C. over 10% palladium on activated carbon (0.20 g) under1 atm of hydrogen for 2 h gave 0.430 g (95% yield) of the title ester aswhite crystals; mp 119–121° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.46 (3H, t, J=7.1 Hz, CH₃), 1.67 (3H, d, J=6.6 Hz, CH₃),3.90 (2H, m, CH₂), 4.13–4.32 (2H, m, CH₂), 4.51 (2H, m, OCH₂), 4.70 (1H,q, J=6.6 Hz, CH), 10.7 (1H, broad, OH). Anal. Calcd for C₁₁H₁₄N₂O₅: C,51.96; H, 5.55; N, 11.01. Found: C, 51.60; H, 5.61; N, 10.70.

3-Benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid. Saponification of intermediate 14, ethyl3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.225 g, 0.65 mmol) as described in the preparation of intermediate 7gave 0.198 g (96% yield) of the title acid as white crystals; mp167–168° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.68(3H, d, J=6.6 Hz, CH₃), 3.93 (2H, m, CH₂), 4.12–4.21 (1H, m, CH),4.27–4.35 (1H, m, CH), 4.70 (1H, q, J=6.6 Hz, OCH), 5.53 (2H, ABq,J_(AB)=11.1 Hz, OCH₂), 7.39 (3H, m, aromatics), 7.55 (2H, m, aromatics).MS (ESI⁺) m/z 317 [M+H⁺]. Anal. Calcd for C₁₆H₁₆N₂O₅: C, 60.75; H, 5.10;N, 8.86. Found: C, 60.65; H, 5.05; N, 8.72.

2-(2-(Methylthio)ethyl)-1,3-dioxolane. A solution of3-(methylthio)propanal (5.2 g, 0.05 mol) and ethyleneglycol (3.4 g.0.055 mol) in 100 mL of benzene was treated with 300 mgp-toluenesulfonic acid and heated at reflux for 4 hrs. The solution wascooled and decanted. Concentration and drying in vacuo provided thetitle compound as a light yellow oil. ¹H NMR (300 MHz, CDCl₃) δ ppm:4.93 (1H, t, J=4.76 Hz) 3.74–4.03 (4H, m) 2.46–2.68 (2H, m) 2.08 (3H, s)1.83–2.00 (2H, m).

4-(Methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanenitrile.Intermediate 17, 2-(2-(methylthio)ethyl)-1,3-dioxolane, (2.96 g, 0.02mol), trimethylsilylcyanide (1.98 g, 0.02 mol) and 20 mg zinc iodidewere combined under N₂ and stirred for 16 hrs at room temperature. Themixture was then concentrated in vacuo to provide 4.9 g (approximately100% yield) of the title compound as a yellow oil. ¹H NMR (300 MHz,CDCl₃) δ ppm: 4.37–4.49 (1H, m) 3.50–3.88 (4H, m) 2.57–2.74 (2H, m)1.98–2.26 (5H, m) 0.06–0.22 (9H, m): LC/MS 198 (−TMS+Na).

4-(Methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanamidine. A solutionof intermediate 18,4-(methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanenitrile, (4.9 g,0.02 mol) in 30 mL of methanol was saturated with ammonia. The flask wasthen sealed and heated in an oil bath at 80–90° C. for 16 hrs. Aftercooling, the flask was opened and the mixture concentrated in vacuo togive the title compound in essentially quantitative yield as a veryviscous oil. ¹H NMR (300 MHz, CDCl₃) δ ppm: 3.94–4.02 (1H, m) 3.76–3.94(3H, m) 3.68–3.77 (2H, m) 3.52–3.62 (2H, m) 2.53–2.67 (2H, m) 2.07 (3H,s) 1.89–2.01 (2H, m); LC/MS 193 (M+H).

Ethyl5-(benzyloxy)-2-(1-(2-hydroxyethoxy)-3-(methylthio)propyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate.Ethyl 2-(benzyloxy)acetate (7.76 g, 0.04 mole) and diethyloxalate (5.84g, 0.04 mole) in 80 mL of tetrahydrofuran were treated with oneequivalent of NaH and a few drops of ethanol. The resulting mixture wasstirred for 1.5 hours after which the solvent was removed under vacuumand replaced with 30 mL of ethanol. Intermediate 19,2-(2-hydroxyethoxy)-4 methylthio)butanamidine, in 30 mL ethanol wasadded to the mixture followed by NaH (60% in mineral oil, 800 mg, 0.02mol). This was stirred for 20 hrs at room temperature and 3 hrs at 60°C. then concentrated under reduced pressure. The residue was dissolvedin CH₂Cl₂ and washed with water. The CH₂Cl₂ layer was dried over MgSO₄,filtered and concentrated under vacuum. Chromatography on silica gel,eluting with 4:1 CH₂Cl₂; ether and ethyl acetate, gave 760 mg of thetitle compound (9% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.24–7.54 (5H,m) 5.17–5.36 (2H, s) 4.50 (1H, m) 4.30 (2H, q, J=7.32 Hz) 3.38–4.00 (4H,m) 2.59 (2H, m) 1.95–2.11 (5H, m) 1.20–1.36 (3H, t, J=7.32 Hz); LC/MSm/z 423 (M+H).

Ethyl3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.To a solution of intermediate 20, ethyl5-(benzyloxy)-2-(1-(2-hydroxyethoxy)-3-(methylthio)propyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(527 mg, 1.25 mmol) and Et₃N (505 mg, 5 mmol) dissolved in 10 mL ofCH₂Cl₂ was added a solution of CH₃SO₂Cl (288 mg, 2.5 mmol) dissolved in2 mL of CH₂Cl₂. This was stirred for 20 hrs then concentrated. The crudeproduct was purified by chromatography on silica gel, using 10:1CH₂Cl₂:ether as eluent, to give the title compound 265 mg (52% yield).(500 MHz, CDCl₃) δ ppm: 7.31–7.55 (5H, m) 5.30 (2H, s) 4.75 (1H, dd,J=3.66 Hz) 4.32–4.40 (2H, q, J=7.17 Hz) 4.13–4.30 (2H, m) 3.75–3.97 (2H,m) 2.20–2.84 (4H, m) 2.06 (3H, s) 1.32 (3H, t, J=7.17 Hz); LC/MS m/z 405(M+H).

3-(Benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid. To a stirred solution of intermediate 21, ethyl3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(97 mg, 0.2 mmol) in 3 mL tetrahydrofuran was added lithium hydroxide(15 mg, 0.6 mmol) in 3 mL water. After 20 min the reaction mixture wasacidified with 1N HCl and extracted with CH₂Cl₂. The extract was driedover MgSO₄, filtered and concentrated to give 82 mg of the titlecompound (88% yield). LC/MS m/e 377.

2-(2-Chloroethoxy)-2-methylpropanenitrile. (Navalokina, R. Et al J. Org.Chem. USSR (Engl. Trans.), 1980, 16, 1382–1386.2) Ramalingam, K. U.S.Pat. No. 4,864,051, 1989.). A 250 mL round bottom flask was charged withZnCl₂ (68.14 g, 0.5 mole) which was then fused by heating under vacuum.After returning to room temperature the material was placed under anatmosphere of N₂. To this was added acetone cyanohydrin (45.66 mL, 0.5mole) followed by 2-chloroethanol (50.24 mL, 0.75 mole) and the mixtureplaced in a preheated oil bath (60° C.). After stirring for 18–20 h at60° C., the reaction mixture was cooled, diluted with water (300 mL) andwashed with CH₂Cl₂ (5×100 mL). The combined CH₂Cl₂ extracts were dried(Na₂SO₄), filtered and concentrated under vacuum to afford the crudeproduct as a yellow liquid. Purification was accomplished by vacuumdistillation (10 mm Hg) using a vigreux column. The fraction boilingbetween 65–75° C. was collected to afford the desired product as acolorless oil (47.1 g, 63.8% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm: 3.85(2H, t, J=5.8 Hz), 3.64 (2H, t, J=5.8 Hz), 1.60 (6H, s).

Additional procedure. ZnCl₂ (352.3 g 2.59 moles) was added to a 2 Lround bottom flask equipped with a mechanical stirrer, nitrogeninlet-outlet, temperature probe, and condenser. Acetone cyanohydrin(110.0 g 1.29 moles) was slowly added to the stirred solid over 30minutes keeping the temperature below 32° C. with external cooling. Tothe slurry, 2-chloroethanol (124.9 g 1.55 moles) was slowly added over20 minutes keeping the temperature below 32° C. with external cooling.Acetone (3.75 g, 64.6 mmoles) was added and the mixture was heated to60° C. After stirring for 4 h at 60° C., the reaction mixture was cooledto 30–35° C., diluted with water (1.10 L) and extracted with CH₂Cl₂(1×440 mL and 1×220 mL). The combined CH₂Cl₂ extracts were washed with0.5M sodium bicarbonate (330 mL), followed by water (3×330 mL). Thedichloromethane solution was concentrated under vacuum to afford crudeproduct (109 g). The crude product was purified by vacuum distillation(10 mm Hg) using a Vigreux column. The fraction boiling at 60–80° C. wascollected to afford 2-(2-chloroethoxy)-2-methylpropanenitrile ascolorless oil (88.7 g).

Intermediate 23b

2-(2-Bromoethoxy)-2-methylpropanenitrile. Dichloromethane (42 mL) andtin tetrachloride (64.9 g, 249 mmol) were added to a 250 mL round bottomflask equipped with a magnetic stirrer, temperature probe, condenser andArgon inlet-outlet. The mixture was cooled to 0–5° C. Acetonecyanohydrin (21.2 g, 249 mmol) was added over 15 min, followed by slowaddition of 2-bromoethanol (46.69 g, 373.6 mmol). The reaction mixturewas stirred at 20–25° C. for 22 h. The mixture was cooled to 0–5° C.,diluted with water (148 mL), and extracted with dichloromethane (3×64mL). The combined CH₂Cl₂ extracts were dried (MgSO₄), filtered andconcentrated under vacuum to afford the crude product as a yellowliquid. The material was purified by vacuum distillation (10 mm Hg)using a Vigreux column. The fraction boiling between 75–85° C. wascollected to afford 2-(2-Bromoethoxy)-2-methylpropanenitrile as acolorless oil (15.09 g).

Ethyl2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate.To a stirred solution of intermediate 23,2-(2-chloroethoxy)-2-methylpropanenitrile (14.7 g, 0.10 mole) and NaI(1.5 g, 10 mmol) in ethanol (50 mL) was added an aqueous solution (50%)of hydroxylamine (18.4 g, 0.30 mole) resulting in an exothermicreaction. Following this the reaction mixture was heated at 80° C. for 2h. Upon cooling to room temperature the solvent was removed. Theresulting residue was dissolved in 1:1 ethanol/H₂O (100 mL) and cooledin an ice bath. To this was added diethyl acetylenedicarboxylate (17.6mL, 0.110 mole) over 10 min. The reaction mixture was allowed to warm toroom temperature and stirred for 1 h. Following this, it was dilutedwith ethyl acetate (250 mL), washed with H₂O (2×100 mL), brine (50 mL),dried over Na₂SO₄, filtered and concentrated to give the crude productas a yellow oil. Flash chromatography on a silica gel column, elutingwith 20–40% ethyl acetate/Hexanes, provided the title compound as aviscous pale yellow oil (15.29 g, 48.6% yield). ¹H NMR (500 MHz, CDCl₃)δ ppm: 4.35–4.28 (2H, m), 4.18–4.12 (2H, m), 3.60–3.56 (1H, m),3.51–3.47 (1H, m), 3.30 (1H, d, J=16.2 Hz), 2.94 (1H, d, J=16.2 Hz),1.52 (3H, s), 1.51 (3H, s), 1.29 (3H, t, J=7.0 Hz), 1.24 (3H, t, J=7.0Hz). LCMS (M+H) calcd for C₁₄H₂₃N₂O₇: 315.16. found: 315.33.

Additional procedures. A solution of2-(2-chloroethoxy)-2-methylpropanenitrile (5.0 g, 33.87 mmol) inanhydrous methanol (33 mL) was added to a 3-necked flask equipped with areflux condenser and argon inlet-outlet. Hydroxylamine hydrochloride(2.82 g, 40.58 mmol, 1.20 eq) was added, followed by powdered sodiumcarbonate (3.95 g, 37.26 mmol, 1.10 eq). The resulting suspension wasallowed to stir at room temperature under argon for 18 hrs. The reactionmixture was then heated at 70° C. in an oil bath for 3 h. The resultingsuspension was allowed to cool to room temperature. The mixture wasfiltered though celite and the filter cake was washed with additionalmethanol. The filtrate was concentrated at reduced pressure to give asemi-solid material which was suspended in chloroform (˜80 mL). Afterstirring for 1 hour, the resulting suspension was filtered throughcelite and the filter cake was washed with additional chloroform. Thefiltrate was concentrated at reduced pressure to give very pale amberoil which crystallized upon standing to crude cyclic amine oxide (5.79g).

The above crude intermediate (3.0 g) was dissolved in hot methanol (3mL). The resulting solution was diluted with ethyl acetate (30 mL). Thesolution was heated at reflux to distill out the bulk of the methanol.Heating was stopped when the distillate reached 75° C. The resultingsolution was allowed to stand 30 min at room temperature and 2.5 h at 5°C. The crystalline solid was collected by filtration, washed with ethylacetate, and dried in vacuo over night at 45–50° C. to give an anhydrousform the cyclic amine oxide as a colorless crystalline solid, 1.94 g.

The crude intermediate above (43.9 g) prepared from a similar experimentdescribed above was dissolved in hot methanol (45 mL). The resultingsolution was diluted with ethyl acetate (400 mL) and water (11.5 mL).The solution was heated at reflux to distill out the bulk of themethanol. Heating was stopped when the distillate reached 71.5° C. Theresulting solution was diluted with 100 mL of ethyl acetate and 1 mL ofmethanol (needed to prevent oiling), seeded with a sample of crystallinemonohydrate and let slowly cool to room temperature over night. Thesolid was collected by filtration, washed with ethyl acetate (100 mL),dried first under nitrogen and in vacuo at room temperature to give themonohydrate form the intermediate cyclic amine oxide as a colorlesscrystalline solid, 27.93 g.

Ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.ZnCl₂ (544.5 g 4.0 moles) was added to a 3 L round bottom flask equippedwith a mechanical stirrer, nitrogen inlet-outlet, temperature probe, andcondenser. Acetone cyanohydrin (170.0 g, 2.00 mol) was slowly added tothe stirred solid over 30 minutes keeping the temperature below 32° C.with external cooling. To the slurry, 2-chloroethanol (193.0 g, 2.40mol) was slowly added over 20 minutes keeping the temperature below 32°C. with external cooling. Acetone (5.80 g, 99.8 mmol) was added and themixture was heated to 60° C. After stirring for 4 h at 60° C., thereaction mixture was cooled to 30–35° C., diluted with water (1.70 L)and extracted with CH₂Cl₂ (1×680 mL and 1×340 mL). The combined CH₂Cl₂extracts were washed with 0.5M sodium bicarbonate (510 mL), followed bywater (3×510 mL). The dichloromethane solution (1210 mL) contained 152 gof 2-(2-chloroethoxy)-2-methylpropanenitrile by GC quantification, GCpurity: 94.7%.

The above dichloromethane solution of2-(2-chloroethoxy)-2-methylpropanenitrile (600 mL, 76 g, 0.515 moles)was added to a 1 L round bottom flask equipped with a mechanicalstirrer, nitrogen inlet, temperature probe, and condenser. The solutionwas concentrated at atmospheric pressure and CH₂Cl₂ was replaced bymethanol (450 mL). The methanol solution was cooled to 20–25° C. andsodium carbonate (21.83 g, 0.206 mmol) was added. An aqueous solution(50%) of hydroxylamine (33.65 mL, 0.617 mol) was added, followed bywater (76 mL). The thin slurry was stirred at 20–25° C. for 18 h. Thenthe reaction mixture was heated to reflux (temperature about 65° C.) for3 h. HPLC analysis showed the solution contained 61.5 g of2,2-dimethyl-4-oxy-5,6-dihydro-2H-1,4-oxazin-3-ylamine; with HPLC purityof 97.2.

The above solution of cyclic amine oxide was cooled to 20–25° C. and thepH (7.0) was adjusted to 7.5 with 0.5M sodium carbonate (20 mL). Themixture was cooled to 0 to −5° C. Diethyl acetylenedicarboxylate (78.85g, 0.463 moles) was added over 1 h keeping the temperature below 5° C.The mixture was stirred for 30 min. Ethyl acetate (760 mL) and water(380 mL) were added. The phases were separated and the aqueous phase wasextracted with ethyl acetate (380 mL). The two ethyl acetate solutionswere combined, washed twice with 50% brine (each 380 mL). The ethylacetate solution contained ethyl2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate.Estimated amount of the titled intermediate in the solution by HPLC was130 g, HPLC AP 79.0. A sample was purified by reverse-phasechromatography giving an oil of 99% purity by HPLC.

Alternate procedure. To a solution of2-(2-chloroethoxy)-2-methylpropanenitrile (5.00 g, 33.87 mmol) inmethanol (30 mL) was added at 20–22° C. a 50% aqueous solution ofhydroxylamine (2.21 mL, 40.58 mmol). Sodium carbonate (1.44 g, 13.59mmol) and finally water (5 mL) were added. The suspension was stirred at20–25° C. for 18 h. The reaction mixture was heated at reflux (65–66°C.) for 3 h. The resulting solution was cooled to 20–25° C. The pH (7.5)required no adjustment. The mixture was cooled to −5° C. and dimethylacetylenedicarboxylate (3.75 mL, 30.56 mmoles) was added slowly overabout 18 min keeping the temperature between −5° C. to 0° C. The mixturewas stirred for 60 min. Additional dimethyl acetylenedicarboxylate (0.4mL, 3.26 mmoles) was added and mixture was stirred another 10 min at 0°C. to complete the reaction as confirmed by HPLC. Ethyl acetate (50 mL)and water (25 mL) were added to the reaction mixture. The phases wereseparated and the aqueous phase was extracted again with ethyl acetate(25 mL). The combined ethyl acetate extracts were washed with about 14%aq. NaCl (2×25 mL). The solvent was removed under vacuum to affordmethyl2-(2-methoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylateas a crude oil (9.4 g, 96.9% yield) with a purity of 71% by HPLC. Asample (0.80 g) was purified by reverse-phase chromatography giving anoil (0.48 g) of 97% purity by HPLC, which crystallized on standing; mp68–69° C.

Ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of intermediate 24, ethyl2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate(31.16 g) in 1,2,4-trimethylbenzene (200 mL) was heated at 180° C. for 5h. The resulting dark reaction solution was cooled then concentrated togive a dark brown paste which was taken up into ethyl acetate (250 mL)and extracted with 0.5 M aq Na₂CO₃ (4×50 mL). The organic layer wasdiscarded and the aqueous layer acidified by carefully adding conc.HCl(20 mL) before being extracted with CH₂Cl₂ (4×50 mL). The combinedCH₂Cl₂ layers were dried (Na₂SO₄), filtered and concentrated to give adark paste which was dissolved in ether (100 mL) and allowed to stand atroom temperature in a open flask. The brown/light yellow solid thatformed was filtered to afford the title compound. The mother liquor thatcontained product was re-processed to afford additional material(combined yield ˜18–20% over two steps). ¹H NMR (500 MHz, CDCl₃) δ:10.55 (1H, s), 4.45 (2H, q, J=7.0 Hz), 4.02 (4H, s), 1.61 (6H, s), 1.43(3H, t, J=7.0 Hz). HRMS (M+H) calcd for C₁₂H₁₇N₂O₅: 269.1138. found:269.1149. Anal calcd for C₁₂H₁₆N₂O₅: C, 53.72; H, 6.01; N, 10.44. Found:C, 53.71; H, 6.04; N, 10.30.

An ethyl acetate solution of the intermediate 24 was placed in a 3 L3-necked flask equipped with a Dean Stark water separator, stirrer, andtemperature probe. Ethyl acetate was removed by distillation andreplaced with 1,2,4-trimethylbenzene (1.14 L). The resulting solutionwas heated at 155° C. for 9 h. The dark reaction mixture was cooled to20–25° C., diluted with water (760 mL) and extracted twice with 0.5MNa₂CO₃ (each 760 mL) the organic layer was discarded. The aqueous phaseswere combined and washed with CH₂Cl₂ (610 mL), phases were separated andthe organic layer was discarded. To the resulting aqueous solution wasadded CH₂Cl₂ (300 mL), and acidified to pH 2.0 with 6M sulfuric acid(130 mL). Phases were separated, and the aqueous phase was extractedwith CH₂Cl₂ (300 mL). The combined CH₂Cl₂ layers were separated in twoequal portions A and B for isolation of intermediate 25.

Portion A isolation without charcoal treatment. The CH₂Cl₂ solution (315mL) was concentrated to 80 mL at atmospheric pressure. Isopropanol (160mL) was added and the solution was concentrated to 140 mL at atmosphericpressure. The solution was cooled slowly with stirring to 20–25° C. Theresulting slurry was further cooled to 0–5° C. and stirred for 2 h. Thesolid was filtered, washed with cold isopropanol (70 mL), dried in vacuoat 40–45° C. to afford ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateas off-white flakes (34.8 g).

Portion B isolation with charcoal treatment. The CH₂Cl₂ solution (315mL) was concentrated to 80 mL at atmospheric pressure. Isopropanol (160mL) was added and the solution was concentrated to 160 mL at atmosphericpressure. Another portion of isopropanol (160 mL) was added followed bycharcoal (10 g). The mixture was stirred at reflux temperature (about82° C.) for 15 min. Charcoal was removed by filtration, the charcoalcake washed with hot (about 80° C.) isopropanol (120 mL) and combinedwith the filtrate. The combined isopropanol solution was concentrated to140 mL at atmospheric pressure. The solution was cooled slowly withstirring to 20–25° C. The resulting slurry was further cooled to 0–5° C.and stirred for 2 h. The solid was filtered, washed with coldisopropanol (50 mL), dried in vacuo at 40–45° C. to afford ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateas off-white flakes (31.3 g).

Alternate procedure. 2-(2-Bromoethoxy)-2-methylpropanenitrile (3.0 g,15.62 mmol) and methanol (21 mL) was added to a 50 mL round bottom flaskequipped with a magnetic stirrer, nitrogen inlet-outlet, temperatureprobe, and condenser. The methanol solution was cooled to 0–5° C. Anaqueous solution (50%) of hydroxylamine (2.13 mL, 39.05 mmol) was added.The reaction mixture was allowed to warm to room temperature and stirredfor 2 h, and then heated at 75° C. for 1.5 h.

The reaction mixture was cooled to 0–5° C. and the pH (7.0) was adjustedto pH (8) with 1M sodium carbonate (3.0 mL). Diethylacetylenedicarboxylate (2.92 g, 17.18 mmoles) was added over 25 minkeeping the temperature below 10° C. The reaction mixture was allowed towarm to room temperature and stirred for 2 h. Ethyl acetate (45 mL) andwater (15 mL) were added. The phases were separated, the ethyl acetatesolution was washed with water (15 mL), dried (MgSO₄) filtered andconcentrated under vacuum to afford a mixture containing ethyl2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylateas the major component an oil (4.6 g).

The above intermediate (4.6 g) and 1,2,4-trimethylbenzene (23 mL) wereadded to a 100 mL 3-necked round bottom flask equipped with a stirrer,and temperature probe. The resulting solution was heated at 155° C. for8 h. The dark reaction mixture was cooled to 20–25° C., and extractedfive times with 0.5M Na₂CO₃ (each 4.6 mL) the organic layer wasdiscarded. The aqueous phases were combined and acidified with conc.HCl(2.3 mL), and then extracted with CH₂Cl₂ (5×4.6 mL). The combined CH₂Cl₂layers were dried (MgSO₄) filtered and concentrated under vacuum to givea dark paste (1.6 g) which was crystallized from methyl-t-butyl ether (3mL). The light brown solid was filtered to afford ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(351 mg).

Intermediate 25b

Methyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of the above crude methyl2-(2-methoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate(8.34 g) in 1,2,4-trimethylbenzene (80 mL) was heated at 155° C. for 9h. The resulting dark mixture was cooled to 20–25° C. and diluted withwater (50 mL). The product was extracted into 0.5M Na₂CO₃ (2×50 mL). Theorganic layer was discarded. The aqueous phases were combined and washedwith CH₂Cl₂ (40 mL). The organic wash was discarded. The aqueoussolution was acidified to pH 2.0 with 6M sulfuric acid (9.0 mL) and theproduct extracted into CH₂Cl₂ (2×20 mL). The combined CH₂Cl₂ layers wereevaporated in vacuo. The residue was redissolved in isopropanol (75 mL)at 75° C. and the solution was treated with activated charcoal (0.85 g)at 75–80° C. for 20 min. The charcoal was removed by filtration andwashed with hot isopropanol. The combined filtrate and wash wasconcentrated in vacuo to 40 mL. The resulting slurry was cooled slowlywith stirring to 10° C. and stirred for 1 h. The solid was filtered,washed with cold isopropanol (10 mL) and dried in vacuo at 40–45° C. toafford methyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateas an off-white crystalline solid (3.68 g).

Ethyl3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.To a stirred solution of intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(2.68 g, 10 mmol) and benzyl bromide (1.43 mL, 12 mmol) in DMF (40 mL)was added K₂CO₃ (2.07 g, 20 mmol). After stirring 48 h at ambienttemperature, the reaction mixture was diluted with ether (100 mL), thenwashed with water (3×30 mL) and brine (20 mL). The organic layer wasdried (Na₂SO₄/activated carbon), filtered and concentrated to give ayellow solid. Trituration with hexanes/ether (9:1) afforded the titlecompound as an off-white solid (2.79 g, 78% yield). ¹H NMR (500 MHz,CDCl₃) δ ppm: 7.48–7.45 (2H, m), 7.37–7.30 (3H, m), 5.25 (2H, s), 4.33(2H, q, J=7.3 Hz), 4.05–3.99 (4H, m), 1.62 (6H, s), 1.29 (3H, t, J=7.3Hz). HRMS (M+H) calcd for C₁₉H₂₃N₂O₅: 359.1607. found: 359.1611. Analcalcd for C₁₉H₂₂N₂O₅: C, 63.67; H, 6.18; N, 7.81. found: C, 63.63; H,6.16; N, 7.78.

3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid. A mixture of intermediate 26, ethyl3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(2.93 g, 8.2 mmol) and LiOH.H₂O (0.84 g, 20 mmol) in 4:1ethanol/tetrahydrofuran (50 mL) was stirred for 2 h at ambienttemperature then concentrated under vacuum. The resulting yellow residuewas treated with 1N HCl (25 mL) providing a precipitate that wasfiltered and dried under vacuum to yield the title compound as a whitepowder (2.68 g, 99% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.54–7.48(2H, m), 7.37–7.27 (3H, m), 5.44 (2H, s), 4.05–3.93 (4H, m), 1.60 (6H,s).). HRMS (M+H) calcd for C₁₇H₁₉N₂O₅: 331.1294. found: 331.1308. Analcalcd for C₁₇H₁₈N₂O₅: C, 61.81; H, 5.49; N, 8.48. found: C, 61.84; H,5.36; N, 8.25.

2-Ethyl-2-hydroxybutanenitrile. To a solution of potassium phosphatemonobasic (140 g, 1.11 mole) in water (250 mL) was added 3-pentanone(75.8 g, 0.88 mole), followed by a solution of sodium cyanide (54 g,1.10 mole) in water (250 mL), and the resulting mixture stirred for 3hours. The mixture was extracted with diethyl ether (1×250 mL, then2×100 mL) and the combined ether layers washed with 1.0 N HCl (200 mL).The ether solution was dried (Na₂SO₄), filtered, and concentratedin-vacuo. The crude product was purified by vacuum distillation (bp 87°C., 10 mmHg) to give the title compound (72.4 g, 3% yield) as a clearoil. ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.71 (1H, s), 1.82 (2H, q, J=7.5Hz), 1.76 (2H, q, J=7.5 Hz), 1.10 (6H, t, J=7.5 Hz). ¹³C NMR (500 MHz,CDCl₃) δ ppm: 121.21, 73.53, 32.81, 8.27.

2-(2-Chloroethoxy)-2-ethylbutanenitrile. Zinc chloride (68.1 g, 0.5 mol)was fused under vacuum as described in the procedure for the synthesisof intermediate 23. The molten zinc was cooled and the evacuated flaskwas flushed with nitrogen. The flask was loaded with intermediate 28,2-ethyl-2-hydroxybutanenitrile, (40.3 g, 0.5 mol) and 2-chloroethanol(50.5 mL, 0.75 mmol) then stirred at 60° C. for 20 hours. The reactionmixture was diluted with water (250 mL) and extracted withdichloromethane (1×250 mL, 4×100 mL). The combined organic layers weredried (sodium sulfate), filtered, and concentrated in-vacuo. The crudeproduct was purified by vacuum distillation (bp 83° C., 10 mmHg) to givethe title compound (52 g) containing unreacted intermediate 28. ¹H NMR(500 MHz, CDCl₃) δ ppm: 3.82 (2H, t, J=5.8 Hz), 3.64 (2H, t, J=5.8 Hz),1.83 (4H, J=7.3 Hz), 1.03 (6H, t, J=7.6 Hz).

Diethyl 2-(2,2-diethyl-3-iminomorpholinooxy)but-2-enedioate. A solutionof the product mixture obtained in the synthesis of intermediate 29,2-(2-chloroethoxy)-2-ethylbutanenitrile, (0.171 mol) in absolute ethanol(150 mL) was added dropwise to a solution of hydroxylamine (50% aqueoussolution, 33.8 mL, 0.51 mol), sodium carbonate (9.1 g, 0.086 mol) andsodium iodide (2.55 g, 0.017 mol) over 15 minutes. The mixture washeated at 80° C. for 3 hours. The reaction was then concentrated to athick paste and azeotroped under vacuum with ethanol/water (1:1, 100mL), water (100 mL) and finally ethanol (100 mL). The residue was takenup in ethanol/water (1:1, 160 mL), cooled (0° C.), and treated withdiethyl acetylenedicarboxylate (30.1 mL, 0.188 mol). The reaction wasstirred at room temperature for 2 hours, then diluted with water (200mL) and ethyl acetate (200 mL). The organic layer was separated, washedwith water (200 mL) and brine (100 mL), then dried (sodium sulfate),filtered and concentrated in-vacuo. The crude product was purified bycolumn chromatography over silica gel, eluting with 10% to 40% ethylacetate in hexanes to afford the title compound (25.7 g) as a yellowoil.

Ethyl9,9-diethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of intermediate 30, diethyl2-(2,2-diethyl-3-iminomorpholinooxy)but-2-enedioate, (25.7 g) in1,2,4-trimethylbenzene (100 mL) was heated at reflux (180° C.) for 16hours. The solvent was then removed in vacuo and the resulting oilplaced in a freezer until crystal formation began. The oil-crystalmixture was triturated with diethyl ether (50 mL) and the solid wascollected by filtration, washing with a small volume of ether to providethe title compound (9.02 g). A second crop (1.62 g) was obtained fromthe filtrate. ¹H NMR (500 MHz, CDCl₃) δ ppm: 10.54 (1H, s), 4.44 (2H, q,J=7.0 Hz), 4.00 (4H, m), 2.00 (2H, m), 1.92 (2H, m), 1.42 (3H, t, J=7.0Hz), 0.85 (6H, t, J=7.3 Hz). ¹³C NMR (500 MHz, CDCl₃) δ ppm: 169.53,157.82, 151.40, 147.58, 125.35, 87.27, 62.62, 58.35, 43.24, 31.06,14.17, 7.79. HRMS [M+H]⁺ calcd for C₁₄H₂₁N₂O₅: 297.14506. found:297.1464.

2-(3-Chloropropoxy)-2-methylpropanenitrle. Zinc chloride (68.1 g, 0.5mol) was fused using the procedure described for the synthesis ofintermediate 23, 2-(2-chloroethoxy)-2-methylpropanenitrile. The moltenzinc was cooled and the flask flushed with nitrogen. The flask wasloaded with acetone cyanohydrin (46 mL, 0.5 mol) and 3-chloropropanol(64 mL, 0.75 mmol) and the reaction mixture stirred at 60° C. for 30hours. The mixture was then diluted with water (200 mL) and extractedwith dichloromethane (1×200 mL and 3×100 mL). The combined organiclayers were dried (sodium sulfate), filtered, and concentrated in-vacuo.The crude product was purified by vacuum distillation (bp 78–84° C., 10mmHg) to give the title compound (41 g) as a 2:1 mixture with residual3-chloropropanol. ¹H NMR (500 MHz, CDCl₃) δ ppm: 3.72 (2H, t, J=5.8 Hz),3.63 (2H, t, J=6.4 Hz), 2.04 (2H, m), 1.57 (6H, br s).

Ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate.A solution of intermediate 32, 2-(3-chloropropoxy)-2-methylpropanenitrle(0.186 mol) in absolute ethanol (40 mL) was added dropwise to a cold (0°C.) solution of hydroxylamine (50% aqueous solution, 17 mL, 0.278 mol),20 mL H₂O, sodium carbonate (9.91 g, 0.093 mol) and sodium iodide (2.80g, 0.019 mol) over 15 minutes. (In an alternative procedure, sodiumcarbonate was omitted from the mixture). The mixture was stirred at roomtemperature for 30 min, then additional hydroxylamine (17 mL, 0.278 mol)was added. The reaction was then heated at 80° C. for 16 hours. Themixture was concentrated to a thick paste which was azeotroped undervacuum with ethanol/water (1:1, 100 mL). The resulting residue was takenup in ethanol/water (1:1, 200 mL), cooled (0° C.), and treated withdiethyl acetylenedicarboxylate (30.1 mL, 0.188 mol) by dropwise additionover 10 min. The reaction was allowed to stir at room temperature for2.5 hours, then diluted with water (300 mL) and ethyl acetate (300 mL).The separated organic layer was washed with water (100 mL) and brine(100 ml), then dried (sodium sulfate), filtered and concentratedin-vacuo. The crude product was purified by silica gel columnchromatography, eluting with 10% to 40% ethyl acetate in hexanes, togive 21.2 g of a yellow oil. A solution of this oil (15.6 g) in1,2,4-trimethylbenzene (300 mL) was heated at reflux (180° C.) for 2.5hours after which the solvent was removed in-vacuo. The resulting oilwas taken up in ethyl acetate (300 mL) and extracted with saturatedaqueous sodium bicarbonate (1×200 mL, then 4×100 mL). The combinedaqueous layers were acidified to pH 1–2 using 6 N HCl then extractedwith ethyl acetate (3×150 mL). The organic extracts were dried (sodiumsulfate), filtered, then concentrated in vacuo. The resulting oil wastriturated with diethyl ether (50 mL) and the resulting solid collectedby filtration and washed with a small volume of ether to afford thetitle compound (2.05 g). A second crop (0.70 g) was obtained from thefiltrate. ¹H NMR (500 MHz, CDCl₃) δ ppm: 10.83 (1H, br), 10.02 (1H, br),4.46 (2H, q, J=7.0 Hz), 3.66 (2H, t, J=6.1 Hz), 3.58 (2H, t, J=5.8 Hz),2.06 (2H, m), 1.55 (6H, s), 1.44 (3H, t, J=7.0 Hz).

Ethyl3-(benzoyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylate.A solution of intermediate 33, ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(0.064 g, 0.2 mmol) in pyridine (1 mL) was treated with benzoicanhydride (0.047 g, 0.2 mmol) and stirred for 1 hr at 60° C. The solventwas removed and the residue taken up in N,N-dimethylformamide (1 mL) andtreated with potassium carbonate (0.036 g, 0.2 mmol). The mixture wasstirred for 1 hr at 80° C., and solvent was removed to give the titlecompound.

3-(Benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylicacid. A suspension of intermediate 33, ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(0.205 g, 0.64 mmol) and anhydrous potassium carbonate (0.361 g, 2.6mmol) in anhydrous dimethylformamide (4 mL) was stirred at 60° C. for 5hours. The reaction mixture was treated with benzyl bromide (0.122 g,0.71 mmol) and stirred for 16 hours. Following this, 2 mL of H₂O wasadded and the mixture stirred for an additional 24 hours. Solvent wasremoved by rotary evaporator and the resulting residue suspended in 0.5N hydrochloric acid (16 mL). The crude product was extracted with ethylacetate (2×15 mL), then dried (sodium sulfate), filtered, andconcentrated to dryness by rotary evaporator to give 0.299 g(Yield>100%) of the title compound as a solid. LC/MS [M+H]⁺=345.21.

3-Hydroxy-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylate.A solution of intermediate 33, ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(7.01 g, 22 mmol) and anhydrous potassium carbonate (9.12 g, 66 mmol) inanhydrous dimethylformamide (50 mL) was stirred at 80° C. for 20 hours.Solvent was removed by rotary evaporator and the residue, dissolved inwater (50 mL), was brought to pH 1 using 6.0 N HCl. The solution wasextracted with ethyl acetate (4×25 mL). The combined organic layers weredried (sodium sulfate) and filtered. The solvent was removed by rotaryevaporator to give the title compound (5.53 g, Yield 89%) as a brownsolid: ¹H NMR (500 MHz, CDCl₃) δ ppm 10.49 (1H, s), 4.56 (2H, br), 4.43(2H, q, J=7.2 Hz), 3.69 (2H, t, J=6.4 Hz), 1.93–1.99 (2H, m), 1.61 (6H,s), 1.42 (3H, t, J=7.2 Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm 169.33,158.30, 153.39, 148.73, 124.45, 82.85, 62.60, 60.71, 38.79, 27.67,27.35, 14.15; HRMS (ESI) calcd for C₁₃H₁₉N₂O₅ (M+H) 283.1294. found283.1305.

(4-Fluoronaphthalen-1-yl)methanamine hydrochloride. A solution of1-cyano-4-fluoronapthalene (1.05 g, 6.12 mmol) and 1.5 mL of HCl (aq.)in absolute ethanol (50 mL) was stirred under a hydrogen atmosphere(balloon) with 10% palladium on carbon (0.20 g) for 16 hours. Thecatalyst was removed by filtration through Celite, and the filtrateconcentrated under vacuum. The resulting solid was triturated with etherand collected by filtration to give the title compound (0.575 g, 44%yield) as an off white solid.

Methyl 2-(aminomethyl)-5-fluorobenzoate trifluoroacetic acid salt.Methyl 2-((tert-butoxycarbonyl)methyl)-5-fluorobenzoate, preparedaccording to literature methods, was treated with trifluoroacetic acidto provide the title compound. Yield 100%; ¹H NMR (300 MHz, DMSO-d₆) δppm: 3.89 (3H, s) 4.32 (2H, q, J=5.61 Hz) 7.51–7.71 (2H, m) 7.78 (1H,dd, J=9.33, 2.38 Hz) 8.13 (2H, brs); LC/MS m/z 184 (M+H)

2-Aminomethyl-5-fluoro-N-methyl-benzamide trifluoroacetic acid salt. Toa solution of tert-butyl 4-fluoro-2-(methylcarbamoyl)benzylcarbamate(7.70 g, 27.3 mmol; prepared from 2-bromo-5-fluorobenzoic acid usingliterature methods) in CH₂Cl₂ (100 mL) was added CF₃CO₂H (25 mL) and themixture stirred at room temperature for 15 min. This was concentrated invacuo and the residue triturated with diethyl ether to obtain 8.0 g(Yield 99%) of the title compound as a white powder. ¹H NMR (300 MHz,D₂O) δ ppm: 2.93 (3H, s) 4.20 (2H, s) 7.35 (1H, dt, J=8.5, 3 Hz) 7.42(1H, dd, J=9.0, 2.7 Hz) 7.57 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 183(M+H).

2-(Aminomethyl)-N-cyclopropyl-5-fluorobenzamide trifluoroacetic acidsalt. A solution of tert-butyl2-(cyclopropylcarbamoyl)-4-fluorobenzylcarbamate (130 mg, 0.42 mmol)prepared according to literature methods, in CH₂Cl₂ (5 mL) was stirredwith trifluoroacetic acid (3 mL) at room temperature for 10 min, thenconcentrated in vacuo to give 140 mg (Yield 100%) of the title compoundas a foam: ¹H NMR (DMSO-d₆, 300 MHz) δ ppm: 0.62 (2H, m, CH₂), 0.73 (2H,m, CH₂), 2.86 (1H, m, CH), 4.02–4.07 (2H, ABq, NCH₂), 7.46 (2H, m,Ar—Hs), 7.58 (1H, m, Ar—H), 8.11 (3H, br, NH3), 8.81 (1H, d, J=4.4 Hz,NH); LC/MS m/z 209 (M+H).

(5-Fluoro-2-methylphenyl)(morpholino)methanone. To a solution ofmorpholine (870 mg, 10 mmol) and triethylamine (1.1 g, 10.8 mmol) inCH₂Cl₂ (15 mL) was added a solution of 5-fluoro-2-methylbenzoyl chloride(1.72 g, 10 mmol) in CH₂Cl₂ (5 mL), dropwise, and the mixture stirredfor 15 min. The mixture was then washed with water, and the organicphase dried (MgSO₄), filtered, and concentrated to obtain 2.19 g (Yield98%) of the title compound as a solid: ¹H NMR (500 MHz, CDCl₃) δ ppm:2.27 (3H, s) 3.24 (2H, d, J=4 Hz) 3.58 (2H, s) 3.79 (4H, dd, J=18, 3.8Hz) 6.88 (1H, dd, J=8.2, 2.8 Hz) 6.92–7.05 (1H, m) 7.18 (1H, dd, J=8.4,5.3 Hz).

(2-(Bromomethyl)-5-fluorophenyl)(morpholino)methanone. A mixture ofintermediate 41, (5-fluoro-2-methylphenyl)(morpholino)methanone, (2.1 g,9.5 mmol) and N-bromosuccinimide (2.0 g, 11 mmol) in CCl₄ (30 mL) washeated at reflux. To this mixture was added benzoylperoxide (242 mg, 1mmol) and the mixture heated at reflux for 2 hrs. After cooling, theinsoluble materials were filtered and the filtrate purified by columnchromatography (SiO₂, 0–10% ether in CH₂Cl₂) to give 1.1 g (Yield 38%)of the title compound as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ ppm:3.31 (2H, t, J=4.94 Hz) 3.55–4.02 (6H, m) 4.56 (2H, dd, J=128.81, 9.51Hz) 6.89 (1H, dd, J=8.23, 2.74 Hz) 6.96–7.12 (1H, m) 7.33–7.49 (1H, m);LC/MS m/z 302 (M+H).

(2-(Azidomethyl)-5-fluorophenyl)(morpholino)methanone. To a solution ofintermediate 42, (2-(bromomethyl)-5-fluorophenyl)(morpholino)methanone,(1.0 g, 3.32 mmol) in dimethylformamide (10 mL) was added sodium azide(230 mg, 3.5 mmol) and the mixture stirred under a nitrogen atmospherefor 1 h. The solvent was evaporated in vacuo, and the residue dissolvedin CH₂Cl₂, then washed with water. The organic phase was dried (Na₂SO₄),filtered, concentrated, and the residue purified by columnchromatography (SiO₂, CH₂Cl₂) to provide 770 mg (Yield 88%) of the titlecompound as an oil: ¹H NMR (300 MHz, CDCl₃) δ ppm: 3.27 (2H, s)3.51–3.65 (2H, m) 3.66–3.97 (4H, m) 4.38 (2H, brs) 6.92 (1H, dd, J=8.2,2.7 Hz) 7.07 (1H, dt, J=8.5, 3 Hz) 7.34 (1H, dd, J=8.4, 5.5 Hz); LC/MSm/z 265 (M+H).

(2-(Aminomethyl)-5-fluorophenyl)(morpholino)methanone hydrochloride. Toa solution of intermediate 43,(2-(azidomethyl)-5-fluorophenyl)(morpholino)methanone, (770 mg, 2.92mmol,) in ethanol (20 mL) was added 4N HCl (1 mL) and 10% Pd—C (100 mg),and the mixture hydrogenated at 1 atm of H₂ for 3 hrs. The catalyst wasremoved by filtration and the filtrate concentrated. The residue waspurified by C18 reverse phase silica gel column chromatography (YMC ODS,0–5% CH₃CN/H₂O) to obtain 350 mg (Yield 44%) of the title compound,(2-(aminomethyl)-5-fluorophenyl)(morpholino)-methanone hydrochloride asa white powder: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 3.0–4.0 (8H, m), 3.78(2H, t, J=5 Hz), 7.32 (1H, dd, J=8.8, 2.6 Hz), 7.35–7.44 (1H, t, J=8.5,3 Hz), 7.75 (1H, dd, J=8.8, 5.5 Hz); LC/MS m/z 239 (M+H).

5-Fluoro-2,N,N-trimethyl-benzenesulfonamide. To a solution of5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) intetrahydrofuran (25 mL) was added, dropwise, a solution of dimethylaminein tetrahydrofuran (2M, 25 mL, 50 mmol) over 15 min. and the mixturestirred for 5 min. The insoluble materials were filtered and thefiltrate concentrated. The residue was purified by column chromatography(SiO₂, 5% ether in CH₂Cl₂) to provide 4.3 g (Yield 90%) of the titlecompound as a clear oil: ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.57 (3H, s)2.82 (3H, s) 2.82 (3H, s) 7.12–7.18 (1H, m) 7.28 (1H, dd, J=8.2, 5.5 Hz)7.59 (1H, dd, J=8.2, 2.1 Hz); LC/MC m/z 218 (M+H).

2-Bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide. Under nitrogen,a mixture of intermediate 45,5-fluoro-2,N,N-trimethyl-benzenesulfonamide, (435 mg, 2.0 mmol) andN-bromosuccinimide (391 mg, 2.2 mmol) in CCl₄ (20 mL) was stirred at80–90° C. for 5 min. To this mixture was added2,2′-azobisisobutyronitrile (AIBN, 100 mg) and stirring continued at80–90° C. for 30 min. After cooling, the insoluble precipitates werefiltered and the filtrate concentrated and purified by columnchromatography (SiO₂, CH₂Cl₂) to provide 440 mg (Yield 74%) of the titlecompound; ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.87 (6H, s) 4.86 (2H, s) 7.28(1H, dd, J=8.55, 2.75 Hz) 7.61–7.65 (2H, m); LC/MC m/z 296/298 (M+H).

2-Azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide. A mixture ofintermediate 46, 2-bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide,(880 mg, 2.97 mmol) and sodium azide (200 mg, 3 mmol) indimethylformamide (4 mL) was stirred at 55–60° C. for 30 min after whichthe solvent was removed in vacuo. The residue was partitioned betweenCH₂Cl₂ and water, and the organic phase was washed with water, dried(Na₂SO₄), filtered and concentrated to provide 670 mg (Yield 87%) of thetitle compound as a yellow oil; ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.84 (6H,s) 4.78 (2H, s) 7.29–7.34 (1H, m) 7.59–7.64 (2H, m).

2-(Aminomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide. To a solutionof intermediate 47,2-azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (660 mg, 2.6mmol) in tetrahydrofuran (10 mL) and water (2 mL) was addedtriphenylphosphine (740 mg, 2.8 mmol), and the mixture stirred undernitrogen for 1 hr. The tetrahydrofuran was evaporated in vacuo and amixture of the residue and 6N HCl (3 mL) in MeOH (5 mL) was heated at80° C. for 20 hrs. This was washed with CH₂Cl₂, and the aqueous phasebasified with dilute NH₄OH and extracted with CH₂Cl₂. The organicextract was dried (Na₂SO₄), filtered and concentrated to provide 210 mg(0.91 mmol, Yield 35%) of the title compound; ¹H NMR (500 MHz, CDCl₃) δppm: 2.84 (6H, s) 4.10 (2H, s) 7.23–7.29 (1H, m) 7.53–7.60 (2H, m);LC/MS m/z 233 (M+H).

5-Fluoro-2,N-dimethyl-benzenesulfonamide. To a solution of5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in acetone(20 mL) was added a 40% aqueous solution of methylamine (4.5 mL, 60mmol) under nitrogen and the mixture stirred for 5 min. Acetone wasremoved in vacuo and the aqueous residue extracted with CH₂Cl₂. TheCH₂Cl₂ extract was dried (Na₂SO₄), filtered, concentrated and theresidue purified by column chromatography (SiO₂, 10% ether in CH₂Cl₂) toprovide 3.9 g (19.2 mmol, Yield 96%) of the title compound as a whitesolid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.59 (3H, s), 2.67 (3H, d, J=5.5Hz), 4.41 (1H, brs), 7.13–7.20 (1H, m), 7.29 (1H, dd, J=8.2, 5.5 Hz),7.69 (1H, J=8.6, 2.1 Hz); LC/MS m/z 204 (M+H).

2-Bromomethyl-5-fluoro-N-methyl-benzenesulfonamide. The title compoundcan be prepared from intermediate 49,5-fluoro-2,N-dimethyl-benzenesulfonamide, according to the methoddescribed for intermediate 46 and purified by column chromatography(SiO₂, 5% ether/CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.64 (3H, d,J=5.19 Hz) 4.91 (1H, d, J=3.66 Hz) 4.98 (2H, s) 7.26–7.30 (1H, m) 7.54(1H, dd, J=8.6, 5.2 Hz) 7.73 (1H, dd, J=8.4, 2.6 Hz); LC/MS m/z 282/284.

2-Azidomethyl-5-fluoro-N-methyl-benzenesulfonamide. The title compoundcan be prepared from intermediate 50,2-bromomethyl-5-fluoro-N-methyl-benzenesulfonamide, according to themethod described for intermediate 47 and purified by columnchromatography (SiO₂, 5% ether-CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃) δ ppm:2.65 (3H, d, J=5.19 Hz) 4.81 (2H, s) 4.86 (1H, d, J=4.6 Hz) 7.27–7.33(1H, m) 7.49 (1H, dd, J=8.2, 5.2 Hz) 7.76 (1H, dd, J=8.2, 2.8 Hz).

2-(Aminomethyl)-5-fluoro-N-methylbenzenesulfonamide hydrochloride. To asolution of intermediate 51,2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide, (560 mg, 2.3 mmol)in ethanol (10 mL) was added 6N HCl (1 mL) and 10% Pd—C (100 mg) and themixture hydrogenated with 1 atm of H₂ for 14 hrs. The catalyst wasremoved by filtration through Celite and the filtrate concentrated invacuo to provide 630 mg (Yield>100%) of the title compound. ¹H NMR (500MHz, DMSO-D6) δ ppm: 4.36 (2H, d, J=5.2 Hz) 7.63–7.70 (2H, m) 7.77–7.83(1H, m) 8.11 (1H, d, J=4.9 Hz) 8.41 (3H, s); LC/MS m/z 219 (M+H).

5-Fluoro-2-methyl-benzenesulfonamide. To a solution of5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in acetone(20 mL) was added, dropwise, concentrated NH₄OH (3 mL) and the resultingmixture stirred for 5 min. Acetone was removed in vacuo and theprecipitates were filtered, washed thoroughly with water and dried invacuo to provide 3.7 g (Yield 98%) of the title compound as a whitesolid; ¹H NMR (500 MHz, DMSO-D6) δ ppm: 2.55 (3H, s) 7.33–7.40 (1H, m)7.40–7.46 (1H, m) 7.54 (2H, s) 7.59 (1H, dd, J=9.2, 2.7 Hz); LC/MS m/z190 (M+H).

2-Bromomethyl-5-fluoro-benzenesulfonamide. The title compound can beprepared from intermediate 53, 5-fluoro-2-methyl-benzenesulfonamide,according to the method described for intermediate 46, and purified bycolumn chromatography (SiO₂, 5% ether/CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃) δppm: 5.01 (2H, s) 5.16 (2H, brs) 7.25–7.31 (1H, m) 7.53 (1H, dd, J=8.5,5.2 Hz) 7.80 (1H, dd, J=8.5, 2.7 Hz). LC/MS m/z 268/270 (M+H).

2-Azidomethyl-5-fluoro-N-methyl-benzenesulfonamide. The title compoundcan be prepared from intermediate 54,2-bromomethyl-5-fluoro-benzenesulfonamide, according to the methoddescribed for the preparation of intermediate 47. ¹H NMR (300 MHz,CDCl₃) δ ppm: 4.82 (2H, s) 5.18 (2H, s) 7.27 (1H, m) 7.45 (1H, dd,J=8.4, 5.5 Hz) 7.79 (1H, dd, J=8.4, 2.6 Hz). LC/MS m/z 253 (M+Na).

2-(Aminomethyl)-5-fluorobenzenesulfonamide hydrochloride. The titlecompound can be prepared from intermediate 55,2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide, according to themethod described for the preparation of intermediate 48. ¹H NMR (500MHz, DMSO-D6) δ ppm: 4.05 (2H, s) 5.05 (3H, br) 7.44 (1H, dt, J=8.5, 3Hz) 7.58 (1H, dd, J=9.2, 2.7 Hz) 7.66 (1H, dd, J=8.5, 5.5 Hz). LC/MS m/z205 (M+H).

5-(2-Bromo-5-fluoro-phenyl)-2-methyl-2H-tetrazole. A mixture of5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol), iodomethane(1.12 g, 10 mmol) and potassium carbonate (1.5 g) in dimethylformamide(5 mL) was stirred at room temperature for 16 hrs, then concentrated invacuo. The residue was purified by column chromatography (SiO₂, CH₂Cl₂)to provide 650 mg (Yield 61%) of the title compound as a white powder.¹H NMR (500 MHz, CDCl₃) δ ppm: 4.45 (3H, s) 7.03–7.11 (1H, m) 7.63 (1H,dd, J=8.9, 3.1 Hz) 7.69 (1H, dd, J=8.9, 5.5 Hz); ¹³C NMR (126 MHz,CDCl₃) δ ppm: 39.86, 116.28, 118.66, 118.76, 130.13, 135.73, 161.74,163.53; LC/MS m/z 257/259.

4-Fluoro-2-(2-methyl-2H-tetrazol-5-yl)-benzonitrile. A mixture ofintermediate 57, 5-(2-bromo-5-fluoro-phenyl)-2-methyl-2H-tetrazole (650mg, 2.53 mmol) and CuCN (224 mg, 2.5 mmol) in dimethylformamide (4 mL)was placed in a sealed tube and heated at 100–110° C. for 20 hrs. Aftercooling, the insoluble material was filtered, and the filtrateconcentrated in vacuo. The residue was dissolved in CH₂Cl₂, washed withaq. 4N HCl and dil. NH₄OH, then dried (MgSO₄), filtered, andconcentrated. The residual solid was purified by column chromatography(SiO₂, CH₂Cl₂) to obtain 375 mg (Yield 73%) of the title compound as anoff-white solid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 4.48 (3H, s) 7.29 (1H,dd, J=7.6, 2.8 Hz) 7.85 (1H, dd, J=8.6, 5.2 Hz) 8.00 (1H, dd, J=9.0, 2.6Hz); LC/MS m/z 204.

(4-Fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)methanamine hydrochloride.A solution of intermediate 58,4-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-benzonitrile, (330 mg, 1.62 mmol)in ethanol (15 mL) was mixed with 6N HCl (1 mL) and 10% Pd—C (200 mg)under nitrogen. The mixture was then stirred under hydrogen (1 atm) for3 hrs. After removing the catalyst, the filtrate was concentrated invacuo to provide 360 mg (Yield 91%) of the title compound as anoff-white solid; ¹H NMR (500 MHz, DMSO-D6) δ ppm: 4.42 (2H, d, J=2.75Hz) 4.49 (3H, s) 7.48–7.56 (1H, m) 7.78 (1H, dd, J=8.7, 5.7 Hz) 7.86(1H, dd, J=9.8, 2.8 Hz) 8.45 (3H, s); LC/MS m/z 208.

5-(2-Bromo-5-fluoro-phenyl)-1-methyl-2H-tetrazole. A mixture of5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol), iodomethane(1.12 g, 10 mmol) and potassium carbonate (1.5 g) in dimethylformamide(5 mL) was stirred at room temperature for 16 hrs, then concentrated invacuo. The residue was purified by column chromatography (SiO₂, CH₂Cl₂)to provide 350 mg (Yield 33%) of the title compound as white crystals.¹H NMR (500 MHz, CDCl₃) δ ppm: 4.00 (3H, s) 7.18–7.25 (2H, m) 7.72 (1H,dd, J=8.4, 5.0 Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm: 34.59, 117.73,119.58, 120.43, 127.57, 135.11, 153.43, 161.69. LC/MS m/z 257/259.

4-Fluoro-2-(1-methyl-2H-tetrazol-5-yl)-benzonitrile. ¹H NMR (300 MHz,CDCl₃) δ ppm: 4.13 (3H, s) 7.38–7.49 (2H, m) 7.86–7.97 (1H, m); LC/MSm/z 204 (M+H).

(4-Fluoro-2-(1-methyl-2H-tetrazol-5-yl)phenyl)methanamine hydrochloride.¹H NMR (500 MHz, DMSO-D6) δ ppm: 4.05 (2H, s) 4.09 (3H, s) 7.58–7.67(1H, m) 7.77 (1H, dd, J=9.3, 2.6 Hz) 7.87 (1H, dd, J=8.7, 5.7 Hz) 8.38(3H, s); LC/MS m/z 208.

3-m-Tolyl-3-trifluoromethyl-3H-diazirine. To a cold stirring solution of3-m-tolyl-3-trifluoromethyl-diaziridine (2.0 g, 10 mmol. prepared usingthe methods described in Doucet-Personeni C. et al., J. Med. Chem.,2001, 44, 3203 and Nassal, M. Liebigs Ann. Chem. 1983, 1510–1523 or inStromgaard, K et al., J. Med. Chem., 2002, 45, 4038–46) in ethanol (20mL) was added triethylamine (1.5 g, 15 mmol). To this mixture was addedtert-butyl hypochlorite (3.25 g, 30 mmol), and the mixture stirred for 5min. This mixture was poured into 10% aqueous sodium sulfite (100 mL),and extracted with ether. The ether extract was washed with brine, dried(MgSO₄), filtered and concentrated. The residue was purified by columnchromatography (SiO₂, pentane) to provide 1.6 g (Yield 80%) of the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm: 2.33 (3H, s) 6.90–7.03 (2H, m)7.15–7.31 (2H, m).

3-(3-Bromomethyl-phenyl)-3-trifluoromethyl-3H-diazirine. To a solutionof intermediate 63, 3-m-tolyl-3-trifluoromethyl-3H-diazirine, (200 mg, 1mmol) in CCl₄ (4 mL) was added N-bromosuccinimide (200 mg, 1.1 mmol,re-crystallized from water), and the stirred mixture heated at 85° C. Tothis was added AIBN (50 mg) and the mixture heated at reflux for anadditional 2.5 hrs. After cooling, the mixture was purified by columnchromatography (SiO₂, pentane) to provide 150 mg (Yield 54%) of thetitle compound as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ ppm: 4.42 (2H,s) 7.10–7.17 (2H, m) 7.31–7.45 (2H, m).

2-[3-(3-Trifluoromethyl-diaziridin-3-yl)-benzyl]-isoindole-1,3-dione. Amixture of intermediate 64,3-(3-bromomethyl-phenyl)-3-trifluoromethyl-3H-diazirine, (140 mg, 0.5mmol) and potassium phthalimide (95 mg, 0.5 mmol) in dimethylformamide(1.5 mL) was stirred at room temperature for 3 hrs. Dimethylformamidewas removed in vacuo. The residue was extracted with CH₂Cl₂, washed withwater, then dried (Na₂SO₄), filtered, and concentrated. The resultingresidue was purified by column chromatography (SiO₂, 1:1 CH₂Cl₂/pentane)to provide 140 mg (Yield 82%) of the title compound as a solid; ¹H NMR(300 MHz, CDCl₃) δ ppm: 4.80 (2H, s) 7.09–7.21 (2H, m) 7.32 (1H, t,J=7.9 Hz) 7.41–7.49 (2H, m) 7.66–7.71 (2H, m) 7.81–7.85 (2H, m); LC/MSm/z 346 (M+H).

(3-(3-(Trifluoromethyl)diaziridin-3-yl)phenyl)methanamine. A stirredsolution of intermediate 65,2-[3-(3-trifluoromethyl-diaziridin-3-yl)-benzyl]-isoindole-1,3-dione,(150 mg, 0.43 mmol) in ethanol (2 mL) was treated with hydrazine hydrate(0.4 mL) at room temperature and the solution stirred for 3.5 hrs. Afterremoving ethanol in vacuo, the residue was partitioned between CH₂Cl₂and water. The aqueous phase was acidified with dilute HCl, and washedwith CH₂Cl₂. The aqueous phase was basified with dilute NaOH, andextracted with CH₂Cl₂. The organic extract was dried (MgSO₄), filtered,and concentrated to obtain 50 mg (Yield 54%) of(3-(3-(trifluoromethyl)diaziridin-3-yl)phenyl)methanamine and(3-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanamine as a 1:1mixture; ¹H NMR (300 MHz, CDCl₃) δ ppm: 3.85 (2H, s) 3.88 (2H, s) 7.08(2H, s) 7.31–7.40 (4H, m) 7.43–7.50 (1H, m, J=6.2 Hz) 7.54 (1H, s);LC/MS m/z 216 (M+H for diazirine) and 218 (M+H for diaziridine).

Intermediates 67–68

To a solution of 2,4-difluorobenzonitrile (10 g, 72 mmol) dissolved intetrahydrofuran (20 mL), and dimethylformamide (40 mL) was added1,2,4-triazole sodium salt (6.3 g, 70 mmol) and the mixture stirred at90° C. for 3 h after which the mixture was filtered and the solventremoved. The resulting residue was adsorbed onto silica gel andintermediates 67 and 68 separated by flash chromatography, eluting with0% to 30% ethyl acetate/hexanes.

4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile. Colorless needles (2.46g, 18% yield) ¹H NMR (500 MHz, CDCl₃) δ: 8.89 (1H, s), 8.19 (1H, s),7.85 (1H, dd, J=8.7, 5.6 Hz), 7.60 (1H, dd, J=8.8, 2.4 Hz), 7.28–7.24(1H, m). LCMS (M+H) calcd for C₉H₆N₄F: 189.05. found: 189.13.

4-(1H-1,2,4-Triazol-1-yl)-2-fluorobenzonitrile. White solid (0.746 g, 6%yield) ¹H NMR (500 MHz, CDCl₃) δ: 8.66 (1H, s), 8.15 (1H, s), 7.79 (1H,dd, J=8.5, 6.7 Hz), 7.69 (1H, dd, J=9.5, 1.8 Hz), 7.65–7.63 (1H, m).LCMS (M+H) calcd for C₉H₆N₄F: 189.05. found: 189.13.

(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride).Intermediate 67, 4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile, (2.46g, 13.13 mmol) was dissolved in hot ethanol (150 mL). To this was added1N HCl (15 mL) followed by 10% Pd—C (200 mg). The mixture was treatedwith H₂ at 55 psi for 4 h in a Parr shaker then filtered over Celite andthe solvent removed under reduced pressure. The resulting residue waspartitioned between ethyl acetate and water. The aqueous phase wasseparated and lyophilized to afford the title compound as a white powder(2.96 g, 99% yield). ¹H NMR (500 MHz, CD₃OD) δ ppm: 9.51 (1H, s), 8.63(1H, s), 7.85 (1H, dd, J=8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz),7.49 (1H, td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd forC₉H₁₀N₄F: 193.08. found: 193.16.

(2-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride. Thetitle compound can be prepared from intermediate 68 according to themethod described for the synthesis of intermediate 69. White powder (79%yield). ¹H NMR (500 MHz, CD₃OD) δ ppm: 9.25 (1H, s), 8.46 (1H, s), 7.80(1H, dd, J=8.6, 5.8 Hz), 7.64 (1H, dd, J=8.8, 2.4 Hz), 7.44 (1H, td,J=8.3, 2.6 Hz), 4.17 (2H, s). LCMS (M+H) calcd for C₉H₁₀N₄F: 193.08.found: 193.16.

Intermediates 71–74

Intermediates 71–74 were prepared using the procedure described for thesynthesis of intermediate 67–70.

4-Fluoro-2-morpholinobenzonitrile ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.55(1H, dd, J=8.5, 6.4 Hz), 6.71 (1H, td, J=8.1, 2.3 Hz), 6.67 (1H, dd,J=11.0, 2.4 Hz), 3.88 (4H, t, J=4.6 Hz), 3.22 (4H, t, J=4.6 Hz). LCMS(M+H) calcd for C₁₁H₁₂N₂OF: 207.09. found: 207.19.

4-Morpholino-2-fluorobenzonitrile. ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.42(1H, dd, J=8.8, 7.6 Hz), 6.63 (1H, dd, J=8.8, 2.4 Hz), 6.56 (1H, dd,J=12.8, 2.4 Hz), 3.84 (4H, t, J=4.9 Hz), 3.28 (4H, t, J=4.9 Hz). LCMS(M+H) calcd for C₁₁H₁₂N₂OF: 207.09. found: 207.19.

(4-Fluoro-2-morpholinophenyl)methanamine hydrochloride. ¹H NMR (500 MHz,CDCl₃) δ ppm: 7.54 (1H, t, J=7.3 Hz), 7.20 (1H, dd, J=10.5, 2.0 Hz),7.05–7.02 (1H, m), 4.28 (2H, s), 3.93 (4H, bs), 3.03 (4H, bs). LCMS(M+H) calcd for C₁₁H₁₆N₂OF: 211.12. found: 211.23.

(2-Fluoro-4-morpholinophenyl)methanamine hydrochloride. ¹H NMR (500 MHz,CD₃OD) δ ppm: 7.73 (1H, t, J=8.2 Hz), 7.62 (1H, d, J=7.6 Hz), 7.58 (1H,d, J=8.2 Hz), 4.26 (2H, s), 4.11 (4H, t, J=4.4 Hz), 3.65 (4H, t, J=4.4Hz). LCMS (M+H) calcd for C₁₁H₁₆N₂OF: 211.12. found: 211.23.

4-Fluoro-2-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzonitrile. To a mixtureof 2,4-difluorobenzonitrile (10.0 g, 72 mmol) and1,1-dioxo-1λ6-[1,2]thiazin-2-ane (8.84 g, 65.4 mmol) in 1:1tetrahydrofuran/dimethylformamide (40 mL) was added potassium carbonate(9.0 g, 65.4 mmol). The mixture was stirred at 90° C. for 18 h thenfiltered and concentrated. The residue was purified by flashchromatography (SiO₂) eluting with 10%–50% ethyl acetate/hexanesfollowed by recrystallization from hot ethyl acetate/hexane to give thetitle compound as white needles (0.537 g, 3% yield). ¹H NMR (500 MHz,CD₃OD) δ ppm: 7.70 (1H, dd, J=8.8, 5.8 Hz), 7.30 (1H, dd, J=8.8, 2.4Hz), 7.15–7.12 (1H, m), 3.27 (2H, t, J=5.3 Hz), 3.33 (2H, t, J=6.1 Hz),2.40–2.35 (2H, m), 2.05–2.01 (2H, m). LCMS (M+H) calcd for C₁₁H₁₆N₂OF:255.06. found: 255.19.

(4-Fluoro-2-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)phenyl)methanaminehydrochloride. Intermediate 75,4-fluoro-2-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzonitrile (1.37 g, 5.4mmol) was dissolved in ethanol (120 mL). To this was added 1N HCl (20mL) and a catalytic amount of 10% Pd—C. The mixture was shaken underhydrogen at 55 psi for 4 h then filtered through Celite and concentratedto give the title compound as white solid (1.58 g, 100% yield). ¹H-NMR(300 MHz, CD₃OD) δ ppm: 7.61 (1H, dd, J=8.4, 6.2 Hz), 7.38 (1H, dd,J=9.3, 2.7 Hz), 7.28 (1H, td, J=8.2, 2.7 Hz), 7.26 (2H, dd, J=21.4, 13.7Hz), 3.93–3.84 (1H, m), 3.50–3.41 (3H, m), 2.40–2.31 (2H, m), 2.04–1.96(2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₆N₂O₆FS: 259.087. found: 259.24.

Intermediates 77–78

To a solution of 1H-1,2,3-triazole (3.5 g, 50.7 mmol) in tetrahydrofuran(10 mL) and dimethylformamide (20 mL) was added, portionwise, NaH (1.3g, 51 mmol, 95%). The mixture was stirred at room temp for 30 min.2,4-Difluorobenzonitrile (7.6 g, 55 mmol) was added and the mixturestirred at 85° C. for 3 h. The white mixture was concentrated andpurified by flash chromatography eluting with 0% to 10% ethylacetate/hexanes to give intermediates 77 and 78.

4-Fluoro-2-1,2,3-triazol-2-yl-benzonitrile. White needles (0.34 g, 3%yield). 1H-NMR (300 MHz, CDCl₃) δ ppm: 7.92 (2H, s), 7.88–7.79 (2H, m),7.19–7.12 (1H, m). LCMS [M+H]+ calcd for C₉H₆N₄F: 189.05. found: 189.12.

2-Fluoro-4-1,2,3-triazol-2-yl-benzonitrile. White solid (0.097 g, 1%yield). ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.03–7.95 (2H, m), 7.86 (2H, s),7.74–7.69 (1H, m).

4-Fluoro-2-1,2,3-triazol-2-yl-benzylamine hydrochloride. Intermediate77, 4-fluoro-2-1,2,3-triazol-2-yl-benzonitrile, (0.34 g, 1.8 mmol) wasdissolved in ethanol (50 mL). 1N HCl (10 mL) was added along with acatalytic amount of 10%-Pd—C. The mixture was shaken under H₂ at 55 psifor 4 h after which it was filtered through Celite and concentrated togive the title compound as the corresponding HCl salt. Yellow solid(0.402 g, 98% yield). ¹H-NMR (500 MHz, CD₃OD) δ ppm: 8.13 (2H, s), 7.87(1H, dd, J=4.9, 2.6 Hz), 7.73 (1H, dd, J=4.9, 2.6 Hz), 7.34 (1H, td,J=8.2, 2.7 Hz), 4.35 (2H, s). LCMS [M+H]⁺ calcd for C₉H₁₀N₄F: 193.08.found: 193.16.

(2-Fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)methanamine: The titlecompound can be prepared from intermediate 78,2-fluoro-4-1,2,3-triazol-2-yl-benzonitrile, according to the procedureprovide for intermediate 79. ¹H-NMR (300 MHz, CD₃OD) δ ppm: 8.05–7.96(2H,m), 8.00 (2H, s), 7.68 (1H, t, J=8.2 Hz), 4.26 (2H, s). LCMS [M+H]⁺calcd for C₉H₁₀N₄F: 193.08. found: 193.14.

Intermediates 81–84

A solution of 2,4-difluorobenzonitrile (7.07 g, 50.8 mmol) and3-methyl-1H-1,2,4-triazole (4.22 g, 50.8 mmol) in N,N-dimethylformamide(45 ml) was treated with powdered anhydrous potassium carbonate (10 g)and the resulting mixture stirred at 22° C. for 18 h. The solid was thenfiltered and the filtrate concentrated in vacuo. The residue was dilutedwith ethyl acetate, washed with water and brine, then dried overanhydrous magnesium sulfate and concentrated. The resulting mixture waspurified by a combination of chromatography on silica gel (elutiongradient of ethyl acetate in hexane) and reversed phase silica gel toyield intermediates 81–84.

4Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile. White crystals(ethyl acetate-hexane); mp 117–118° C. ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.54(3H, s, CH₃), 7.24 (1H, m, CH), 7.62 (1H, dd, J=2.5 Hz and J=9.1 Hz,CH), 7.84 (1H, dd, J=5.6 Hz and J=8.6 Hz, CH), 8.82 (1H, s, CH). Anal.Calcd for C₁₀H₇FN₄: C, 59.40; H, 3.49; N, 27.71. Found: C, 59.25; H,3.32; N, 27.81.

4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile. White crystals(ethyl acetate-hexane); mp 120–121° C. ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.56(3H, s, CH₃), 7.30 (1H, dd, J=2.5 Hz and J=8.1 Hz, CH), 7.39 (1H, m,CH), 7.91 (1H, dd, J=5.5 Hz and J=8.6 Hz, CH), 8.06 (1H, s, CH). Anal.Calcd for C₁₀H₇FN₄: C, 59.40; H, 3.49; N, 27.71. Found: C, 59.35; H,3.70; N, 27.77.

2-Fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile. White crystals(ethyl acetate-hexane); mp 133–134° C. ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.52(3H, s, CH₃), 7.61 (1H, dd, J=2 Hz and J=9.1 Hz, CH), 7.67 (1H, dd, J=2Hz and J=9.6 Hz, CH), 7.79 (1H, dd, J=6.5 Hz and J=8.6 Hz, CH), 8.56(1H, s, CH). Anal. Calcd for C₁₀H₇FN₄: C, 59.40; H, 3.49; N, 27.71.Found: C, 59.42; H, 3.24; N, 28.41.

2-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile. White crystals(ethyl acetate-hexane); mp 89–90° C., ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.69(3H, s, CH₃), 7.49–7.55 (2H, m, 2×CH), 7.83 (1H, dd, J=6.8 Hz and J=8.8Hz, CH), 8.00 (1H, s, CH). Anal. Calcd for C₁₀H₇FN₄: C, 59.40; H, 3.49;N, 27.71. Found: C, 59.17; H, 3.22; N, 28.01.

(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride salt. Hydrogenation of intermediate 81,4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile, (0.680 g, 3.36mmol) gave 0.720 g (88% yield) of the title hydrochloride salt as awhite solid. ¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.40 (3H, s, CH₃), 4.02 (2H,m, NCH₂), 7.50 (1H, m, CH), 7.62 (1H, dd, J=2.8 Hz and J=9.3 Hz, CH),7.84 (1H, dd, J=6.1 Hz and J=9.1 Hz, CH), 9.00 (1H, s, CH). HRMS (ESI⁺)calculated for C₁₀H₁₂FN₄ [M+H⁺]: 207.1046. found: 207.1047.

(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride salt. Hydrogenation of intermediate 82,4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile, (0.244 g, 1.20mmol) gave 0.290 g (100% yield) of the title hydrochloride salt as awhite solid. ¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.42 (3H, s, CH₃), 3.78 (2H,m, NCH₂), 7.58 (1H, m, CH), 7.67 (1H, dd, J=2.8 Hz and J=9.3 Hz, CH),7.90 (1H, dd, J=6.0 Hz and J=8.6 Hz, CH), 8.22 (1H, s, CH). HRMS (ESI⁺)calculated for C₁₀H₁₂FN₄ [M+H⁺]: 207.1046. found: 207.1041.

(2-Fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride salt. Hydrogenation of intermediate 83,2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile, (0.220 g, 1.09mmol) gave 0.260 g (98% yield) of the title hydrochloride salt as awhite solid. ¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.38 (3H, s, CH₃), 4.09 (2H,m, NCH₂), 7.75–7.8 (2H, m, 2×CH), 7.83 (1H, dd, J=2 Hz and J=9 Hz, CH),9.29 (1H, s, CH). MS (ESI⁺) m/e 207 [M+H⁺].

4-Fluoro-2-imidazol-1-yl-benzonitrile. To a solution of imidazole (4.45g, 65.4 mmol) in tetrahydrofuran (30 mL) and dimethylformamide (10 mL)was added potassium carbonate (9.95 g, 72 mmol) and the mixture wasstirred for 30 min at room temp. To this was added2,4-difluorobenzonitrile (10.0 g, 72 mmol) and the mixture stirred at90° C. for 3 h then at room temp for 2 days. The mixture was filteredand concentrated and the residue was purified by flash chromatography(SiO₂) eluting with 20% to 70% ethyl acetate/hexane to give the titlecompound as white needles (1.1 g, 9% yield). ¹H-NMR (500 MHz, CDCl₃) δppm: 7.94 (1H, s), 7.84 (1H, dd, J=8.7, 5.6 Hz), 7.37 (1H, t, J=8.7, 5.6Hz), 7.37 (1H, t, J₁=1.4 Hz), 7.29 (1H, t, J=1.1 Hz), 7.27–7.21 (2H, m).LCMS [M+H]⁺ calcd for C₁₀H₇N₃F: 188.058. found: 188.12.

(4-Fluoro-2-(1H-imidazo-1-yl)phenyl)methanamine) hydrochloride. Thetitle compound can be prepared from intermediate 88,4-fluoro-2-imidazol-1-yl-benzonitrile, according to the method providedfor intermediate 79. Yellow solid, ¹H-NMR (500 MHz, CD₃OD) δ ppm: 9.39(1H, s), 7.98 (1H, d, J=1.5 Hz), 7.92–7.89 (2H, m), 7.63–7.59 (2H, m),4.11 (2H, s). LCMS [M+H]⁺ calcd for C₁₀H₁₁N₃F: 192.09. found: 192.15.

1-(2-Cyano-5-fluoro-phenyl)-1H-1,2,4-triazole-3-carboxylic acid methylester. To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (27 g,215 mmol) in dimethylformamide (170 mL) was added sodium hydride (5.53g, 95%, 217 mmol) and the mixture was stirred for 30 min. Added to thiswas 2,4-difluorobenzylnitrile (30 g, 217 mmol) and the resulting mixturestirred at room temp for 60 h. The mixture was diluted with water andfiltered to remove solids. The solution was extracted with ethyl acetateand the organic phase was washed with water (3×'s) and brine, then dried(Na₂SO₄) and concentrated. The resulting residue was purified by flashchromatography (SiO₂) eluting with 30% tetrahydrofuran/20% CH₂Cl₂/50%hexane to give the title compound as white needles (5.34 g, 10% yield).¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.92 (1H, s), 7.85 (1H, dd, J=8.8, 5.5Hz), 7.67 (1H, dd, J=8.8, 2.6 Hz), 7.34–7.27 (1H, m), 40.3 (3H, s). LCMS[M+H]⁺ calcd for C₁₁H₈N₄FO₂: 247.06. found: 247.11.

Methyl1-(2-(aminomethyl)-5-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate. Thetitle compound can be prepared from intermediate 90,1-(2-cyano-5-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid methylester ¹H-NMR (300 MHz, CD₃OD) δ ppm: 9.15 (1H, s), 7.80 (1H, dd, J=8.8,5.9 Hz), 7.71 (1H, dd, J=8.8, 2.6 Hz), 7.46 (1H, td J=8.2, 2.6 Hz), 4.19(2H, s), 4.03 (3H, s). LCMS [M+H]⁺ calcd for C₁₁H₁₂N₄O₂: 251.09. found:251.17.

3-Fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzonitrile. To asolution of 1,1-dioxo-1λ6-[1,2]thiazin-2-ane (1.90 g, 14.4 mmol)dissolved in tetrahydrofuran (8 mL) and dimethylformamide (2 mL) wasadded sodium hydride (0.36 g, 95%, 14.4 mmol) and the mixture stirredfor 20 min. To this was added 2,3-difluorobenzonitrile (2.0 g, 14.4mmol) and the mixture stirred at 90° C. for 2 h. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with water and brine then concentrated. The solid residue wastriturated with 1:1 ethyl acetate/hexane to give the title compound as apale brown solid (0.47 g, 13% yield). ¹H-NMR (500 MHz, CDCl₃) δ ppm:7.47–7.45 (1H, m), 7.32–7.36 (2H, m), 4.08–4.02 (1H, m), 3.57 (1H, td,J=13.0, 3.7 Hz), 3.40–3.34 (1H, m), 3.32–3.27 (1H, m), 2.44–2.32 (2HF,m), 2.04–1.97 (2H, m), 1.90–1.84 (1H, m). LCMS [M+H]⁺ calcd forC₁₁H₁₂N₂FO₂S: 255.28. found: 255.13.

3-Fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzylamine hydrochloride.The title compound can be prepared from intermediate 92,3-fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzonitrile according tothe procedure provided for intermediate 79. White solid, ¹H-NMR (500MHz, CD₃OD) δ ppm: 7.56–7.52 (1H, m), 7.40–7.34 (2H, m), 4.31 (2H, s),3.98–3.93 (1H, m), 3.68–3.64 (1H, m), 3.42–3.39 (2H, m), 2.42–2.37 (2H,m), 2.03–1.92 (2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₆N₂O₂FS: 259.09.found: 259.18.

3-Fluoro-2-1,2,4-triazol-1-yl-benzonitrile. A mixture of2,3-difluorobenzylnitrile (2.27 g, 16.3 mmol) and triazole sodium salt(1.33 g, 14.8 mmol) in tetrahydrofuran (5 mL) and dimethylformamide (10mL) was stirred at 85° C. for 4 h. After concentration, the residue waspurified by flash chromatography (SiO₂) eluting with 25%–50% ethylacetate/hexane. The isolated product was recrystallized from hot ethylacetate/hexane to give the title compound as white needles (1.51 g, 54%yield). ¹H-NMR (500 MHz, CDCl₃) δ ppm: 8.50 (1H, d, J=2.4 Hz), 8.25 (1H,s), 7.69–7.67 (1H, m), 7.60–7.57 (2H, m). LCMS [M+H]⁺ calcd for C₉H₆N₄F:189.16. found: 189.14.

(3-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine. The titlecompound can be prepared from intermediate 94,3-fluoro-2-1,2,4-triazol-1-yl-benzonitrile. ¹H-NMR (500 MHz, CD₃OD) δppm: 9.61 (1H, d, J=2.9 Hz), 8.79 (1H, s), 7.82–7.74 (1H, m), 7.67–7.57(2H, m), 4.14–4.13 (2H, m). LCMS [M+H]⁺ calcd for C₉H₁₀N₄F: 193.08.found: 193.16.

5-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile. A suspension of2,5-diflurobenzonitrile (4.5 g, 32.35 mmol) and 1,2,4-triazole sodiumsalt (3.6 g, 40 mmol) in dimethylformamide (40 mL) was heated at 80° C.for 15 h. The reaction mixture was then cooled, diluted with CH₂Cl₂ (200mL), washed with water (3×30 mL) and brine (30 mL), then dried (Na₂SO₄),filtered and concentrated to give a white solid which was purified byflash column chromatography (SiO₂) using 1:1 to 3:1 ethylacetate/Hexanes to afford the title compound (2.98 g, 49% yield) as awhite powder. ¹H NMR (500 MHz, CDCl₃) δ: 8.70 (1H, s), 8.18 (1H, s),7.76 (1H, dd, J=9.0, 4.8 Hz), 7.55 (1H, dd, J=7.3, 2.8 Hz), 7.51–7.47(1H, m). LCMS (M+H) calcd for C₉H₆FN₄: 189.17. found: 189.10.

(5-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride. Asolution of intermediate 96,5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile (2.94 g, 15.59 mmol) inethanol (100 mL) and 1N HCl (50 mL) was degassed by bubbling N₂. Then,110% Pd/C was added, the flask evacuated and vented to H₂ three timesand left on a Parr shaker under a H₂ atmosphere (40 psi). After 6 h, thereaction mixture was filtered, concentrated and the aqueous solutionlyophilized to afford the title compound (4.07 g, 98%) as a whitepowder. LCMS (M+H) calcd for C₉H₁₀FN₄: 193.09. found: 193.15.

2-(1H-1,2,4-Triazol-1-yl)benzonitrile. A suspension of2-fluorobenzylnitrile (3.0 g, 25 mmol) and 1,2,4-triazole sodium salt(2.4 g, 27 mmol) were stirred in tetrahydrofuran (7 mL) anddimethylformamide (14 mL) at 95° C. for 18 h. After cooling andconcentrating, the product was crystallized from hot CH₂Cl₂/hexane (1:1)to give the title compound as a white solid (4.25 g, 100% yield). ¹H-NMR(300 MHz, CDCl₃) δ ppm: 8.74 (1H, s), 8.16 (1H, s), 7.82 (1H, dd, J=4.9,1.3 Hz), 7.77–7.25 (2H, m), 7.57–7.51 (1H, m). LCMS [M+H]⁺ calcd forC₉H₇N₄: 171.06. found: 171.12.

(2-(1H-1,2,4-Triazol-1-yl)phenyl)methanamine hydrochloride. Intermediate98, 2-(1H-1,2,4-triazol-1-yl)benzonitrile (4.25 g, 25 mmol) wasdissolved in ethanol (50 mL) and 1N HCl (25 mL). 10% Pd—C (1 g) wasadded and the mixture shaken under H₂ for 2 h at 50 psi. Afterfiltration through Celite and concentration, the residue was trituratedwith diethyl ether and the title compound was collected as a whitesolid. (3.94 g, 75% yield). ¹H-NMR (300 MHz, CD₃OD) δ ppm: 9.01 (1H, s),8.32 (1H, s), 7.78–7.64 (4H, m), 4.15 (2H, s). LCMS [M+H]⁺ calcd forC₉H₁₁N₄: 175.09. found: 175.17.

2-(1,1-Dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzonitrile. Added to a solutionof 1,1-dioxo[1,2]thiazinane (3.37 g, 25 mmol) in dimethylformamide (35mL) was sodium hydride (0.675 g, 25 mmol, 95%) and the mixture stirredat room temperature for 15 min. 2-Fluorobenzonitrile (3.37 mL, 31.3mmol) was added and the mixture stirred at 80° C. for 18 h. The mixturewas cooled, diluted with water and extracted with ethyl acetate. Theorganic phase was washed with water and brine, then dried (Na₂SO₄) andconcentrated. The residue was purified by flash chromatography (SiO₂)eluting with 10%–100% ethyl acetate/hexane. The isolated solid wasrecrystallized from hot ethyl acetate/hexane (2:1) to give the titlecompound as white crystals (4.15 g, 70% yield). ¹H-NMR (300 MHz, CDCl₃)δ ppm: 7.70 (1H, dd, J=7.7, 1.1 Hz), 7.64–7.53 (2H, m), 7.41 (1H, td,J=7.3, 1.6 Hz), 3.72 (2H, t, J=5.5 Hz), 3.32 (2H, t, J=6.0 Hz),2.40–2.32 (2H, m), 2.05–1.97 (2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₂N₂O₂S:237.06. found: 237.10.

2-(1,1-Dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzylamine hydrochloride.Intermediate 100, 2-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzonitrile,(2.63 g, 11.14 mmol) was dissolved in ethanol (150 mL) and 1N HCl (13mL). Added to this was 10% Pd—C (0.5 g) and the mixture shaken under H₂at 55 psi for 24 h. Filtration through Celite followed by concentrationgave the title compound as a white solid (2.93 g, 95% yield). ¹H-NMR(300 MHz, CD₃OD) δ ppm: 7.61–7.47 (4H, m), 4.30 (2H, q, J=13.7 Hz),3.96–3.87 (1H, m), 3.49–3.36 (3H, m), 2.40–2.31 (2H, m), 2.05–1.96 (2H,m). LCMS [M+H]⁺ calcd for C₁₁H₁₇N₂SO₂: 241.10. found: 241.10.

(3,5-Difluoropyridin-2-yl)methanamine hydrochloride. A mixture of3,5-difluoropicolinonitrile (1.4 g, 10 mmol), conc.HCl (12 ml) and 10%Pd—C (200 mg) in 1:1 ethanol/tetrahydrofuran was shaken under a hydrogenatmosphere (50 psi) for 5 h. The reaction mixture was filtered and theethanol removed in vacuo. The remaining solution was lyophilized toafford an off-white solid (2.16 g, 100% yield). LCMS (M+H) calcd forC₆H₇F₂N₂: 145.06. found: 145.12.

(5-Chloropyridin-2-yl)methanamine. A solution of 5-chloropicolinonitrile(3.8 g, 27.43 mmol), conc.HCl (3 mL) and 10% Pd—C (1.0 g) in ethanol(100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. Thereaction mixture was filtered, concentrated and the resulting residuetaken up in satd NaHCO₃ (50 mL) and extracted with CH₂Cl₂ (4×25 mL). Thecombined CH₂Cl₂ layers were dried (Na₂SO₄), filtered and concentrated togive the title compound as a yellow oil (2.0 g, 51% yield). LCMS (M+H)calcd for C₆H₈ClN₂: 143.04. found: 143.07. ¹HNMR (500 MHz, CDCl₃) δ ppm:8.56–8.51 (1H, br d), 7.66–7.60 (1H, m), 7.28–7.14 (1H, m), 3.97 (2H,s), 1.72 (2H, s).

2-(Bromomethyl)-5-fluorobenzonitrile. N₂ was passed through a mixture of5-fluoro-2-methylbenzonitrile (28.51 g, 211 mmol), NBS (41.31 g, 232mmol) and AIBN (2.5 g, 15 mmol) in CCl₄ (845 mL) for 10 min after whichthe reaction was heated at reflux for 8 h. After standing at roomtemperature overnight, the reaction mixture was filtered and the filtercake washed with CCl₄ (500 mL). The combined filtrate was evaporated togive a yellow oil. Flash chromatography (SiO₂) using 5–25% ethylacetate/Hexanes as eluent afforded the title compound (29.74 g, 66%yield) as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.55 (1H, dd,J=8.6, 5.2 Hz), 7.37 (1H, dd, J=7.9, 2.8 Hz), 7.32–7.28 (1H, m), 4.61(2H, s).

2-((1,3-Dioxoisoindolin-2-yl)methyl)-5-fluorobenzonitrile. To a stirredsolution of intermediate 104, 2-(bromomethyl)-5-fluorobenzonitrile(29.72 g, 139 mmol) and phthalimide (32.69 g, 222 mmol) indimethylformamide (300 mL) was added Cs₂CO₃ (67.87 g, 208 mmol). Afterstirring vigorously for 1 h, the reaction mixture was poured into water(1.2 L). The precipitated product was filtered, washed with water (600mL) and methanol (150 mL) to give a white solid. The solid was taken upinto 1 L of water/methanol (2:1) to which was added K₂CO₃ (12 g) and themixture stirred at 40° C. After 30 min., the mixture was cooled andfiltered. The filter cake was washed with water (500 mL), and driedunder vacuum to afford the title compound (38.91 g, 94% yield) as awhite powder. ¹H NMR (500 MHz, CDCl₃) δ: 7.89 (2H, dd, J=5.5, 3.1 Hz),7.76 (5.5, 3.1 Hz), 7.41 (1H, dd, J=8.6, 5.2 Hz), 7.38 (1H, dd, J=7.9,2.8 Hz), 7.24 (1H, td, J=8.2, 2.8 Hz), 5.06 (2H, s). LCMS (M+H) calcdfor C₁₆H₁₀FN₂O₂: 281.07. found: 281.15.

tert-Butyl 2-cyano-4-fluorobenzylcarbamate. A suspension of intermediate105, 2-((1,3-dioxoisoindolin-2-yl)methyl)-5-fluorobenzonitrile, (5.6 g,20 mmol) in dimethylformamide (20 mL) was warmed until it was dissolved.To this was added tetrahydrofuran (100 mL) and the mixture placed in apre-heated (70° C.) oil bath. Hydrazine monohydrate was added to thisand the reaction stirred for 8 h. The resulting white slurry was left atambient temperature overnight. To this slurry was addeddi-tert-butyldicarbonate (6.55 g, 30 mmol) and the mixture stirred for 6h at room temperature. The reaction mixture was diluted with ether (100mL), filtered and the filtrate treated with activated carbon at 40° C.After filtration and concentration the crude product was purified byflash chromatography, using 20–30% ethyl acetate/Hexanes as eluent, toprovide the title compound (2.88 g, 58% yield) as a light yellow powder.¹H NMR (500 MHz, CDCl₃) δ: 9.46 (1H, br s), 7.61 (1H, dd, J=7.9, 2.1Hz), 7.34 (1H, dd, J=8.2, 4.6 Hz), 7.22 (1H, td, J=8.6, 2.4 Hz), 4.71(2H, s), 1.59 (9H, s). LCMS (M+H) calcd for C₁₃H₁₆FN₂O₂: 251.12. found:251.22.

2-(Aminomethyl)-5-fluorobenzonitrile trifluoroacetic acid salt. Around-bottom flask was charged with intermediate 106, tert-butyl2-cyano-4-fluorobenzylcarbamate, (1.9 g, 7.591 mmol) then treated withtrifluoroacetic acid (20 ml) at room temperature. After 1 h, thereaction mixture was concentrated to give a yellow oil which wasdissolved in CHCl₃ and re-concentrated to afford the title compound(2.01 g, 100% yield) as a pale yellow solid. LCMS (M+H) calcd forC₈H₈FN₂: 151.07. found: 151.08.

(2,5-Dibromo-4-fluorophenyl)methanamine. A solution of2,5-dibromo-4-fluorobenzyl bromide (0.350 g, 1 mmol) in 7M NH₃/MeOH washeated in a sealed tube at 100° C. for 2 h. The reaction mixture wascooled and concentrated to give a white solid which was dissolved inCH₂Cl₂ and treated with Et₃N (1 mL) then concentrated. The resultingresidue was triturated with ethyl acetate (25 mL), filtered andconcentrated to give the title compound (0.291 g) as a pale yellow oil.HRMS (M+H) calcd for C₇H₇Br₂FN: 283.94. found: 283.93.

4-Fluoro-2-methylsulfanyl-benzylamine. Under N₂,4-fluoro-2-(methylthio)benzonitrile (1.67 g, 0.1 mol) was dissolved in20 mL tetrahydrofuran and treated with 10 mL 2M BH₃.Me₂S. This washeated at 60° C. for 2 hrs. Heating was discontinued and 5 mL MeOH wascautiously added, followed by the cautious addition of 4 mL 6N HCl.Additional H₂O (20 mL) was added followed by ethyl acetate. The layerswere separated. The aqueous layer was made basic with 1N NaOH andextracted with CH₂Cl₂. The extracts were dried (MgSO₄), filtered,concentrated and dried in vacuo to give 1.3 g of the title compound as asolid (Yield=76%). ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.20–7.31 (1H, m) 6.90(1H, dd, J=2.4 Hz) 6.75–6.86 (1H, m) 3.86 (2H, s) 2.47 (3H, s); LC/MSm/z 172.

2-(Aminomethyl)-5-fluorobenzenamine hydrochloride.2-Amino-4-fluorobenzonitrile (Fritz Hunziker et al. Eur. J. Med. Chem.1981, 16, 391) (0.300 g, 1.68 mmol), was dissolved in acetic anhydride(5 mL) and the solution was stirred at 23° C. for 18 h. An additionalportion of acetic anhydride (3 mL) was added to dissolve theN-(2-cyano-5-fluorophenyl)acetamide. Then palladium (10% on charcoal)(25 mg) was added and the mixture was agitated under H₂ (34 psi) for 72h. The Pd—C was removed by filtration on Celite and the filtrateconcentrated in vacuo to afford a bis-acetamide: LCMS (M+H)⁺ m/z 225.This was heated at reflux with HCl (6N, 10 mL) for 30 min. The acid wasremoved under reduced pressure to give a solid which was crystallizedfrom MeOH-ether to afford the title compound (0.120 g, 51% yield). ¹HNMR (400 MHz, MeOD) δ ppm: 7.51 (1H, m), 6.96(2H, m), 4.20 (2H, s).

4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzonitrile. A 48 mL pressure vesselcontaining 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol),2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs₂CO₃ (2.28 g, 7.0 mmol) and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) (0.231 g,0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd₂dba₃ was introduced and the reaction mixture heated at 105° C. for 48 h.The mixture was cooled, diluted with ethyl acetate or dioxane, and thenfiltered through Celite. The resulting mixture was concentrated in vacuoand subjected to column chromatography on silica gel with hexanes:ethylacetate (3:7) gradient as the eluent to afford the title compound as awhite solid (0.887 g, 87% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.69(1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07 (1H, ddd,J=2.5, 7.6, 8.6 Hz), 3.96 (2H, t, J=7.0 Hz), 2.62 (2H, t, J=8.1 Hz),2.30–2.22 (2H, m); LCMS (⁺ESI, M+H⁺) m/z 205.

4-Fluoro-2-(2-oxopiperidin-1-yl)benzonitrile. The title compound can beprepared according to the procedure provided for intermediate 111 ¹H NMR(400 MHz, CDCl₃) δ ppm: 7.71 (1H, dd, J=5.7, 8.7 Hz), 7.14–7.06 (1H, m),7.08 (1H, dd, J=2.4, 9.0 Hz), 3.65 (2H, t, J=5.7 Hz), 2.60 (2H, t, J=6.3Hz), 2.05–1.95 (4H, m); LCMS (⁺ESI, M+H⁺) m/z 219.

4-Fluoro-2-(2-oxoazepan-1-yl)benzonitrile. The title compound can beprepared according to the procedure provided for intermediate 111. ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.68 (1H, dd, J=5.8, 8.6 Hz), 7.08 (1H, ddd,J=2.5, 7.6, 8.6 Hz), 7.01 (1H, dd, J=2.5, 9.0 Hz), 3.77–3.76 (2H, m),2.75–2.72 (2H, m), 1.91–1.86 (6H, m); LCMS (⁺ESI, M+H⁺) m/z 233.

N-(2-Cyano-5-fluorophenyl)-N-methylacetamide. The title compound can beprepared according to the procedure provided for intermediate 111 ¹H NMR(400 MHz, CDCl₃) δ ppm: 7.79–7.75 (1H, m), 7.32–7.19 (1H, m), 7.10–7.07(1H, m), 3.42 (0.6H, brs), 3.30 (2.4H, s), 2.32 (0.6H, brs), 1.91 (2.4H,s); LCMS (⁺ESI, M+H⁺) m/z 193; HPLC: 94% (220 nm).

2-(2-Oxoazetidin-1-yl)benzonitrile. The title compound can be preparedaccording to the procedure provided for intermediate 111. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 8.02 (1H, d, J=8.4 Hz), 7.76 (1H, dd, J=1.5, 7.8Hz), 7.69–7.65 (1H, m), 7.23 (1H, s), 4.04 (2H, t, J=4.8 Hz), 3.16 (2H,t, J=4.8 Hz). LCMS (⁺ESI, M+H⁺) m/z 173.

2-(2-Oxooxazolidin-3-yl)benzonitrile. The title compound can be preparedaccording to the procedure provided for intermediate 111. ¹H NMR (400MHz, CDCl₃) δ ppm: 7.71 (1H, dd, J=1.5, 7.6 Hz), 7.68–7.63 (1H, m), 7.58(1H, d, J=7.6 Hz), 7.38 (1H, dt, J=1.3, 7.6 Hz), 4.57 (2H, t, J=7.8 Hz),4.21 (2H, t, J=7.8 Hz); LCMS (⁺ESI, M+H⁺) m/z 189.

4-Fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile. A 48 mL pressure vesselcontaining 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol),2-oxazolidone (0.390 g, 4.50 mmol), K₂CO₃ (0.970 g, 7.0 mmol) andxantphos (0.231 g, 0.40 mmol) in dioxane (10 mL) was degassed with argonfor 15 min. Pd₂ dba₃ (0.140 g, 0.15 mmol) was introduced and then thereaction mixture was heated at 70° C. for 18 h. The mixture was cooled,diluted with dioxane, and then filtered through Celite. The resultingmixture was concentrated in vacuo and subjected to column chromatographyon silica gel with hexanes:ethyl acetate (1:1) to (3:7) gradient as theeluent to afford the title compound as a white solid (0.460 g, 50%yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.73 (1H, dd, J=5.8, 8.6 Hz),7.43 (1H, dd, J=2.5, 9.6 Hz), 7.11 (1H, ddd, J=2.5, 7.5, 8.7 Hz), 4.60(2H, t, J=7.1 Hz), 4.29 (2H, t, J=7.1 HJz); LCMS (⁺ESI, M+H⁺) m/z 207.

3-(2-(Aminomethyl)-5-fluorophenyl)oxazolidin-2-one hydrochloride. ¹H NMR(400 MHz, MeOD) δ ppm: 7.73 (1H, dd, J=6.0, 8.6 Hz), 7.43 (1H, dd,J=2.5, 9.5 Hz), 7.11 (1H, ddd, J=2.5, 7.5, 8.6 Hz), 4.64 (2H, t, J=7.7Hz), 4.17 (2H, t, J=7.7 Hz), 4.14 (2H, s); LCMS (⁺ESI, M+H⁺) m/z 211.

4-Fluoro-2-(2-oxoazetidin-1-yl)benzonitrile. The title compound can beprepared according to the procedure provided for intermediate 117 ¹H NMR(400 MHz, CDCl₃) δ ppm: 8.06 (1H, dd, J=10.7, 2.6 Hz), 7.58 (1H, dd,J=8.6, 6.3 Hz), 7.87 (1H, td, J=8.6, 2.5 Hz), 4.25 (2H, t, J=5.0 Hz),3.26 (2H, t, J=5.0 Hz); LCMS (⁺ESI, M+H⁺) m/z 191.

1-(2-(Aminomethyl)-5-fluorophenyl)azetidin-2-one hydrochloride. ¹H NMR(400 MHz, DMSO/D₂O) δ ppm: 7.54 (1H, dd, (t), J=8.6 Hz), 7.25 (1H, dd,J=10.8, 2.5 Hz), 7.17 (1H, td, J=8.6, 2.5 Hz), 4.12 (2H, s), 3.79 (2H,t, J=4.6 Hz), 3.09 (2H, t, J=4.6 Hz); LCMS (⁺ESI, M+H⁺) m/z 195.

(R)-2-(2-((tert-Butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile.The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.68 (1H, dd,J=5.8, 8.8 Hz), 7.19 (1H, dd, J=2.5, 9.1 Hz), 7.11–7.07 (1H, m),4.46–4.42 (1H, m), 3.55(2H, d, J=3.3 Hz), 2.72–2.52 (2H, m), 2.43–2.33(1H, m), 2.09–2.01 (1H, m), 0.81 (9H, s), −0.04 (3H, s), −0.07 (3H, s);LCMS (⁺ESI, M+H⁺) m/z 349.

(S)-2-(2-((tert-Butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile.The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.68 (1H, dd,J=5.8, 8.6 Hz), 7.19 (1H, dd, J=2.5, 9.4 Hz), 7.11–7.07 (1H, m),4.46–4.43 (1H, m), 3.55(2H, d, J=3.3 Hz), 2.72–2.52 (2H, m), 2.43–2.33(1H, m), 2.09–2.01 (1H, m), 0.81 (9H, s), −0.04 (3H, s), −0.07 (3H, s);LCMS (⁺ESI, M+H⁺) m/z 349.

4-Fluoro-2-(thiazol-2-ylamino)benzonitrile. The title compound can beprepared according to the procedure provided for intermediate 111. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 9.21 (1H, s), 8.39–8.35 (1H, m), 7.97 (1H,d, J=5.0 Hz), 7.23–7.13 (3H, m); LCMS (⁺ESI, M+H⁺) m/z 220.

4-Fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzonitrile. The titlecompound can be prepared according to the procedure provided forintermediate 111. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.30 (1H, dd, J=6.5,8.8 Hz), 7.96 (1H, s), 7.26–7.19 (2H, m), 2.64 (3H, s); LCMS (⁺ESI,M+H⁺) m/z 235.

1-(2-(Aminomethyl)-5-fluorophenyl)piperidin-2-one hydrochloride salt. Toa stirred solution of intermediate 112,4-fluoro-2-(2-oxopiperidin-1-yl)benzonitrile (150 mg, 0.69 mmol) in H₂O(10 mL) was added ethanol (10 mL) 10% palladium on charcoal (50 mg) and1N HCl (2.1 mL, 20.6 mmol). The reaction was shaken in a Parr systemunder H₂ (40 psi) for 1 h. Then the Pd/C catalyst was removed byfiltration on Celite and the filtrate was concentrated in vacuo to yielda solid. Toluene (2×50 mL) was added to the solid and the solution wasevaporated in vacuo. LCMS (M+H)⁺ m/z 170.

1-Bromo-4-fluoro-2-methoxybenzene. To a mixture of2-bromo-5-fluorophenol (10 g, 50.8 mmol) and iodomethane (11.2 g, 78.7mmol) in dimethylformamide (100 mL) was added potassium carbonate (10.9g, 79 mmol) and the mixture stirred at room temperature for 3 hrs. Themixture was diluted with water (100 mL) and extracted with ether (50mL×3). The combined extracts were washed with brine, dried overanhydrous magnesium sulfate, and concentrated in vacuo to obtain 11.3 gof 1-bromo-4-fluoro-2-methoxybenzene as an amber colored oil.

4-Fluoro-2-methoxybenzonitrile. To a solution of intermediate 126,1-bromo-4-fluoro-2-methoxybenzene (9.0 g) in N-methylpyrrolidone (100mL, Sure Seal; Aldrich) was added CuCN (6.6 g, 73.7 mmol, 1.8 eq.;Aldrich), and the mixture stirred at 180° C. under anhydrous nitrogenfor 5.5 hrs. After cooling, 14% aqueous NH₄OH (330 mL) was added andstirring continued for 45 min at room temperature. The mixture wasextracted with ether (100 mL×3), and the combined extracts washedsequentially with dilute aqueous NH₄OH, dilute HCl and brine, then dried(MgSO₄), and concentrated to provide the title compound (5.2 g, Yield85% in 2 steps) as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ ppm: 3.91(3H, s, OMe), 6.69 (1H, dd, J=2.3 Hz, J=10.5 Hz, Ar—H), 6.72 (1H, dt,J=2.5 Hz, J=J=8.0 Hz, Ar—H), 7.55 (1H, dd, J=6.5 Hz, J=8.5 Hz, Ar—H);¹³C NMR (CDCl₃, 125.8 Hz) δ ppm: 56.49, 98.16, 100.06, 100.27, 108.31,108.50, 115.83 135.37, 135.46, 163.25, 163.34 165.47, 167.50. Ananalytical sample was obtained by trituration with ether: Anal. calcdfor C₈H₆FNO: C, 63.57; H, 4.00; N, 9.26. found: C, 63.36; H, 3.91; N,9.16.

4-Fluoro-2-methoxybenzylamine hydrochloride. To a mixture ofintermediate 127, 4-fluoro-2-methoxybenzonitrile, (800 mg, 5.3 mmol) andconc.HCl (0.53 mL, 6.36 mmol, 1.2 eq.) in ethanol (20 mL) was added 10%Pd—C (100 mg; Aldrich), and the mixture hydrogenated at 1 atm hydrogenfor 15 hrs at room temperature. To this mixture was added an additionalamount of conc.HCl (1 mL) and 10% Pd—C (200 mg) and the reaction allowedto continue for another 40 hrs. The mixture was filtered through Celiteand the filtrate concentrated in vacuo to dryness. The residue wastriturated with ether to provide the title compound (895 mg, Yield 88%)as a white powder: ¹H NMR (CDCl₃, 500 MHz) δ ppm: 3.84 (3H, s, OMe),3.91 (2H, d, J=5.5 Hz, N—CH₂), 6.81 (1H, dt, J=2.5 Hz, J=J=8.5 Hz,Ar—H), 6.99 (1H, dd, J=2.5 Hz, J=11.3 Hz, Ar—H), 7.47 (1H, dd, J=7 Hz,J=8.5 Hz, Ar—H); ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm: 36.76, 56.03, 99.30,99.51 106.28, 106.45, 117.93, 117.95, 131.60, 131.69, 158.56, 158.64,162.28, 164.22. HRMS (ESI) calcd for C₈H₁₁FNO (M+H) 156.0825. found156.0830.

4-Fluoro-2-hydroxybenzonitrile. A mixture of intermediate 127,4-fluoro-2-methoxybenzonitrile, (4.53 g, 30 mmol;) and AlCl₃ (5.0 g,37.6 mmol; Aldrich) in anhydrous toluene (30 mL) was stirred atapproximately 130° C. for 18 hrs. After cooling, ice water (˜50 mL) wasadded and the resulting mixture extracted with ether (20 mL×2). Thecombined extracts were washed sequentially with water and brine, thendried (MgSO₄), and concentrated in vacuo to provide the title compound(3.90 g, 28.5 mmol, Yield 95%) as a white solid: ¹H NMR (DMSO-d₆, 300MHz) δ ppm: 6.74–6.84 (2H, m, Ar—Hs), 7.71 (1H, dd, J=7 Hz, J=8.5 Hz,Ar—H), 11.64 (1H, s, OH); ¹³C NMR (DMSO-d₆, 75.5 Hz) δ ppm: 95.13102.45, 102.78, 106.53, 106.83 115.53, 134.68, 134.84, 161.41, 161.58,163.00, 166.35. HRMS (ESI−) calcd for C₇H₃NOF (M−H) 136.0199. found136.0199.

4-Fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile. To a solution ofintermediate 129, 4-fluoro-2-hydroxybenzonitrile, (685 mg, 5 mmol) indimethylformamide (8 mL, Sure Seal; Aldrich) was added NaH (200 mg, 5mmol; 60% oil dispersion; Aldrich), and the mixture stirred for 5 minunder an anhydrous nitrogen atmosphere. To this was added4-(2-chloroacetyl)morpholine (900 mg, 5.5 mmol, 1.1 eq.; AvocadoOrganics), and stirring continued at room temperature for 21 hrs. Thereaction was quenched by careful addition of water (30 mL). Theresulting mixture was extracted with CH₂Cl₂ (25 mL×2). The combinedextracts were washed with brine, dried (MgSO₄) and concentrated. Theresidue was triturated to obtain 1.10 g (4.17 mmol, Yield 83%) of thetitle compound as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ ppm: 3.63(2H, t, J=4 Hz, NCH₂), 3.67 (1H, m, OCH), 3.72 (1H, m, OCH), 4.86 (2H,s, OCH₂), 6.80–6.86 (2H, m, Ar—Hs), 7.61 (1H, dd, J=8.5 Hz, 6.1 Hz,Ar—H); ¹³C NMR (CDCl₃, 125.77 Hz) δ ppm: 42.63, 46.04, 66.80, 68.33,98.45, 98.47, 101.57, 101.79, 109.56, 109.74, 115.42, 135.48, 135.57,161.26, 161.35, 114.79, 165.23, 167.28. HRMS calcd for C₁₃H₁₄N₂O₃F (M+H)265.0988. found 265.0998.

2-(2-(Aminomethyl)-5-fluorophenoxy)-1-morpholinoethanone hydrochloride.A solution of intermediate 130,4-fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile, (500 mg, 1.89 mmol)in warm ethanol (30 mL) and ethyl acetate (30 mL) was mixed withconc.HCl (0.32 mL, 3.78 mmol, 2 eq.). To this was added 10% Pd—C (100mg; Aldrich), and the mixture was hydrogenated at 1 atm of hydrogen for20 hrs at room temperature. To this mixture was added an additionalamount of 10% Pd—C (50 mg) and stirring continued for another 7 hrs. Themixture was filtered through Celite and the filtrate concentrated invacuo to dryness. The residue was triturated with ethyl acetate, thenwith ethanol to obtain the title compound (168 mg, Yield 29%) as anoff-white powder: ¹H NMR (CD₃OD, 500 MHz) δ ppm: 3.55 (2H, t, J=5 Hz,NCH₂), 3.62 (2H, t, J=5 Hz, NCH₂), 3.70 (2H, t, J=5 Hz, OCH₂), 3.75 (2H,t, J=5 Hz, OCH₂), 4.17 (2H, s, NCH₂), 5.17 (2H, s, OCH₂), 6.82 (1H, dt,J=2.5, 8.5 Hz, Ar—H), 7.05 (1H, dd, J=2.5, 10.5 Hz, Ar—H), 7.43 (1H, dd,J=6.5, 8.5 Hz, Ar—H); ¹³C NMR (CD₃OD, 125.77 Hz) δ ppm: 39.40, 42.49,44.97, 66.11, 66.46, 66.59, 101.38, 101.59, 108.40, 108.57, 118.40,132.53, 132.62, 158.43, 158.52, 63.87, 165.83, 168.27. HRMS (ESI) calcdfor C₁₃H₁₈N₂O₃F (M+H) 269.1301. found 269.1301.

Dimethyl-carbamic acid 2-cyano-5-fluoro-phenyl ester. Under N₂, astirred solution of intermediate 129, 4-fluoro-2-hydroxybenzonitrile(685 mg, 5.00 mmol), dimethylcarbamoyl chloride, and triethylamine (606mg, 6 mmol) in dichloroethane (10 mL) was heated at reflux for 20 hrs.The cooled mixture was diluted with dichloroethane (10 mL) washed withwater, and brine. The organic layer was separated, dried (Na₂SO₄),concentrated, and the residue purified by column chromatography (SiO₂,5% ethyl acetate-CH₂Cl₂) to provide 700 mg (Yield 67%) of the titlecompound as a white crystalline solid: ¹H NMR (CDCl₃, 500 MHz) δ ppm:3.03 (3H, s, NMe), 3.15 (3H, s, NMe), 6.99 (1H, dt, J=2.5 Hz, 8.5 Hz,Ar—H), 7.23 (1H, dd, J=2.5 Hz, 9.5 Hz, Ar—H), 7.61 (1H, dd, J=9 Hz, 6Hz, Ar—H); ¹³C NMR (CDCl₃, 125.77 Hz) δ ppm: 36.76, 37.06, 102.84,102.86, 111.59, 111.79, 113.24, 113.42, 114.99, 134.36, 134.45, 152.54,155.06, 155.16, 164.26, 166.31. HRMS (ESI) calcd for C₁₀H₁₀N₂O₂F (M+H)209.0726. found 209.0722.

Dimethyl-carbamic acid 2-aminomethyl-5-fluoro-phenyl esterhydrochloride. To a solution of intermediate 132, dimethyl-carbamic acid2-cyano-5-fluoro-phenyl ester, (340 mg, 1.63 mmol) in ethyl acetate (20mL) and ethanol (20 mL), was added conc.HCl (0.4 mL) and 10% Pd—C (100mg) and the mixture hydrogenated in a Parr Shaker at 55 psi of hydrogenfor 20 hrs. The reaction mixture was filtered through Celite, and thefiltrate concentrated in vacuo to give an oil which was partitionedbetween ethyl acetate (10 mL) and water (10 mL). After separation, theaqueous phase was washed with additional ethyl acetate (5 mL). Thecombined extracts were concentrated in vacuo to dryness. The residualoil was triturated with ether to provide 145 mg (Yield 38%) of the titlecompound, as a tan powder: ¹H NMR (CD₃OD, 500 MHz) δ ppm: 3.06 (3H, s,NMe), 3.21 (3H, s, NMe), 4.11 (2H, s, NCH₂), 7.13 (2H, m, Ar—Hs), 7.60(1H, m, Ar—H); ¹³C NMR (CD₃OD, 125.77 Hz) δ ppm: 36.03, 36.25 37.58,110.79, 110.99, 113.26, 113.43, 122.32, 132.18, 132.25, 151.55, 154.72,162.69, 164.67. HRMS (ESI) calcd for C₁₀H₁₃N₂O₂F (M+H) 213.1039. found213.1039.

2-(Benzyloxy)-4-fluorobenzonitrile. Benzyl alcohol (13 mL, 125 mmol) wasslowly added to a stirred suspension of NaH (95%, 2.86 g, 113 mmol) intoluene (200 mL) at room temperature. After 30 min,2,4-difluorobenzonitrile (15.3 g, 110 mmol; Aldrich) was added all atonce and stirring continued overnight (18 h). After this, the reactionmixture was washed with water (2×25 mL) and brine (25 ml). The organiclayer was dried (Na₂SO₄), filtered and concentrated to give a whiteslurry which was triturated with hexanes and filtered to afford thetitle compound as a white solid (20.34 g, 81% yield). ¹H NMR (500 MHz,CDCl₃): 7.59–7.55 (1H, m), 7.45–7.34 (5H, m), 6.75–6.71 (2H, m), 5.19(2H, s); ¹³C NMR (125.76 MHz, DMSO-d₆) δ ppm: 71.16, 98.75, 101.54,101.75, 108.66, 108.84, 115.83, 127.16, 128.58, 128.94, 135.03, 135.44,135.54, 162.22, 162.31, 165.26, 167.29. LCMS calcd for C₁₄H₁₁FNO: 228.2.found: 228.0.

2-Hydroxy-4-fluoro-benzylamine hydrochloride. A solution of intermediate134, 2-(benzyloxy)-4-fluorobenzonitrile, (9.03 g, 39.7 mmol) in ethanol(100 mL) and ethyl acetate (100 mL) was stirred with 10% palladium oncarbon (1.67 g,) and concentrated hydrochloric acid (12 mL, 144 mmol)under a hydrogen atmosphere (60 psi) for four days. The catalyst wasremoved by filtration through Celite, and the filtrate was concentrated.The crude product was triturated with ether and the resulting solidcollected by filtration to give the title compound (5.24 g, 74% yield)as a pale orange solid. ¹H NMR (500 MHz, DMSO-D6) δ ppm: 10.81 (1H, s),8.18 (3H, s), 7.36 (1H, t, J=7.3 Hz), 6.79 (1H, dd, J=10.8, 2.6 Hz),6.66 (1H, dt, J=8.5, 2.3 Hz), 3.90 (2H, d, J=5.2 Hz).

(2,2-Diethoxyethyl)(o-tolyl)sulfane. In ethanol (50 mL) was dissolvedsodium metal (1.6 g, 66 mmol) at 23° C. 2-Methylbenzenethiol (8.1 mL, 68mmol) was slowly added to this solution, followed by bromoacetaldehydediethylacetal (9.50 mL, 63 mmol). The reaction mixture was stirred atreflux for 18 h. The solvent was then evaporated in vacuo and theresidue was washed with H₂O (100 mL) and extracted with ether (100 mL).The organic solution was dried (MgSO₄), concentrated in vacuo andpurified by distillation to afford the title compound (13.48 g, 82%yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.33 (1H, d, J=7.9 Hz), 7.16–7.08(3H, m), 4.65 (1H, t, J=5.6 Hz), 3.66 (2H, q, J=7.0 Hz), 3.55 (2H, q,J=7.0 Hz), 3.09 (2H, d, J=5.6 Hz), 2.38 (3H, s), 1.20 (6H, t, J=7.0 Hz).LCMS (M+H)⁺ m/z 241 (t=2.65 min.).

7-Methylbenzo[b]thiophene. To a solution of intermediate 136,(2,2-diethoxyethyl)(o-tolyl)sulfane (0.58 g, 2.41 mmol) in chlorobenzene(20 mL) was added polyphosphoric acid. The reaction mixture was stirredat reflux for 18 h. Water (100 mL) was then added and the organicmaterial was extracted with CH₂Cl₂ (2×50 mL). The organic solution wasdried (MgSO₄) and concentrated in vacuo to afford 335 mg (94% yield) ofthe title compound: ¹H NMR (400 MHz, CDCl₃) δ: 7.68 (1H, d, J=7.8 Hz),7.43 (1H, d, J=5.4 Hz), 7.36 (1H, d, J=5.4 Hz), 7.30 (1H, dd, J=7.8, 7.1Hz), 7.14 (1H, d, J=7.1 Hz), 2.58 (3H, s); LCMS (M+H)⁺ m/z 148.

7-(Bromomethyl)benzo[b]thiophene. To a solution of intermediate 137,7-methylbenzo[b]thiophene (1.0 g, 6.5 mmol) in CCl₄ (20 mL) was addedbenzoyl peroxide (1.1 g, 4.54 mmol) followed by portionwise addition ofNBS (1.15 g, 6.5 mmol). The reaction mixture stirred at reflux whileirradiating with a 250 W lamp. The reaction mixture was stirred atreflux for 3 h. The solution was cooled, filtered and the solventevaporated in vacuo. The residue was subjected to column chromatographyon silica gel with hexanes as the eluent to afford the title compound(0.570 g, 33% yield): ¹H NMR (400 MHz, CDCl₃) δ: 7.80 (1H, dd, J=7.8,1.7 Hz), 7.49 (1H, d, J=5.4 Hz), 7.40–7.33 (3H, m), 4.78 (2H, s). LCMS(M+H)⁺ m/z 209.

Benzo[b]thiophen-7-ylmethanamine hydrochloride. To intermediate 138,7-(bromomethyl)benzo[b]thiophene (0.20 g, 0.96 mmol) was added amethanolic solution saturated with ammonia (30 mL). The reaction mixturewas heated in a steal bomb at 70° C. for 18 h. The solvent wasevaporated in vacuo and the residue was dissolved in MeOH (10 mL). HCl(1M in ethanol, 1 mL) was added to the solution and the solvents wereremoved in vacuo to afford the title compound (0.177 g, 99% yield); LCMS(M+H)⁺ m/z 164.

Intermediates 140–148

The synthesis of intermediates 140–148 provides representativeprocedures for the synthesis of other compounds in the invention.

N-{4-Fluoro-2-(methylcarbamoyl)benzyl}-3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A mixture of intermediate 27,3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid (0.172 g, 0.54 mmol) and intermediate 39,2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.177g, 0.60 mmol) in dichloromethane (10 ml) was treated at 22° C. withtriethylamine (0.17 ml, 1.22 mmol) followed bybenzotriazole-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP) (0.340 g, 0.65 mmol). After 3 h, the reaction mixture wasdiluted with ethyl acetate, washed with saturated sodium bicarbonate andbrine then dried over anhydrous magnesium sulfate. Evaporation of thesolvent followed by chromatography of the residue on silica gel (elutiongradient ethyl acetate 50–100% in toluene) gave 0.260 g (100% yield) ofthe title amide as a white solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.70(3H, d, J=6.6 Hz, CH₃), 3.01 (3H, d, J=4.7 Hz, NCH₃), 3.89 (2H, m, CH₂),4.14 (1H, m, CH), 4.29 (1H, m, CH), 4.53 (2H, d, J=6.7 Hz, NCH₂), 4.69(1H, q, J=6.6 Hz, OCH), 5.35 (2H, s, OCH₂), 6.69 (1H, broad q, NH), 7.09(1H, m, aromatic), 7.16 (1H, m, aromatic), 7.32 (3H, m, aromatics), 7.42(1H, m, aromatic), 7.47 (2H, m, aromatics), 8.61 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₅H₂₆FN₄O₅ [M+H⁺]: 481.1887. found: 481.1884.

N-(4-fluorobenzyl)-3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 22 (82 mg, 0.22 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (152 mg, 0.4 mmol) in 1 mL dimethylformamidewas stirred for 20 min under N₂. 4-Fluorobenzylamine (38 mg, 0.3 mmol)was then added and stirring continued for 16 hrs. The dimethylformamidewas evaporated under reduced pressure and the remaining residuedissolved in CH₂Cl₂. The resulting solution was washed with dil HCl. Thesolvent was removed under reduced pressure and the crude productpurified by chromatography (SiO₂, ethyl acetate) to provide the titlecompound (70 mg, Yield 66%). LC/MS m/e 484 (M+H).

3-(Benzyloxy)-2-(6-fluoro-1-oxoisoindoline-2-carbonyl)-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one.To a stirred suspension of intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid, (1.65 g, 5 mmol) in CH₂Cl₂ (15 mL) was added a catalytic amount ofdimethylformamide and 10 mL of a 2 M oxalylchloride in CH₂Cl₂. After 30min., the resulting clear yellow solution was concentrated to afford alight brown solid. This solid was dissolved in CH₂Cl₂ (50 mL) and addedto a stirred mixture of intermediate 107,2-(aminomethyl)-5-fluorobenzonitrile trifluoroacetic acid salt, (1.77 g,5.97 mmol) and diethylisopropylamine (2.6 mL, 15 mmol) in CH₂Cl₂ (100mL). After 1 h, the clear brown reaction mixture was concentrated andthe resulting residue dissolved in ethyl acetate (200 mL) then washedsequentially with water (25 mL), 1N HCl (25 mL), water (25 mL) and brine(25 mL). The combined aqueous layers were extracted with CH₂Cl₂ (3×50mL). The combined organic phases were dried (Na₂SO₄), filtered,concentrated and purified by flash chromatography (SiO₂), using 30–50%ethyl acetate/Hexanes as eluent to afford the title compound (0.331 g,14% yield) as a yellow powder. ¹H NMR (500 MHz, CDCl₃) δ: 7.48–7.45 (1H,m), 7.88 (2H, d, J=7.9 Hz), 7.30 (2H, d, J=7.0 Hz), 7.12 (2H, t, J=7.6Hz), 7.05–7.01 (1H, m), 5.22 (2H, s), 4.77 (2H, s), 4.06 (4H, s), 1.59(6H, s). HRMS (M+H) calcd for C₂₅H₂₃FN₃O₅: 464.1622. found: 464.1628.

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A 25 mL round-bottom flask was charged with intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid, (0.991 g, 3.0 mmol), intermediate 39,2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt(1.185 g, 4.0 mmol), 4-dimethylaminopyridine (DMAP, 1.1 g, 9.0 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 1.722 g, 4.5 mmol). Dimethylformamide (20 mL)was added and the mixture stirred for 1 h at ambient temperature. Afterthis, the reaction mixture was diluted with ethyl acetate (100 mL) thenwashed with water (3×25 mL) and brine (25 mL). The organic layer wasdried (Na₂SO₄), filtered, concentrated and purified by flashchromatography (SiO₂), eluting with hexanes/ethyl acetate (1:1 to 1:3)followed by ethyl acetate, to afford the title compound as an off-whitesolid (1.48 g, 100% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm: 8.49 (1H, t,J=6.1 Hz), 7.48–7.46 (2H, m), 7.43 (1H, dd, J=8.5, 5.5 Hz), 7.31–7.27(3H, m), 7.12 (1H, dd, J=8.9, 2.7 Hz), 7.05 (1H, td, J=8.2, 2.7 Hz),6.52 (1H, br s), 5.26 (2H, s), 4.53 (2H, d, J=6.4 Hz), 4.01 (2H, t,J=4.9 Hz), 3.96 (2H, t, J=4.9 Hz), 2.97 (3H, d, J=4.9 Hz), 1.62 (6H, s).HRMS (M+H) calcd for C₂₆H₂₈FN₄O₅: 495.2044. found: 495.2032.

N-(4-Fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid, (1.50 g, 4.54 mmol) and HATU (2.07 g, 5.45 mmol) in anhydrousdimethylformamide was stirred for 20 minutes under a nitrogen atmosphereat room temperature. To the solution was added intermediate 135,2-hydroxy-4-fluoro-benzylamine hydrochloride, (1.05 g, 5.9 mmol)followed by DMAP (1.39 g, 11.4 mmol), and the reaction mixture stirredat 60° C. for 90 minutes. The solvent was removed in vacuo and the cruderesidue purified by flash column chromatography (SiO₂), eluting with40%–60% ethyl acetate in hexanes to give the title compound (1.31 g, 64%yield) as a solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 9.69 (1H, br s), 8.18(1H, t, J=6.3 Hz), 7.44 (2H, dd, J=6.6, 2.6 Hz), 7.30–7.35 (3H, m), 7.00(1H, dd, J=8.2, 6.7 Hz), 6.68 (1H, dd, J=10.4, 2.4 Hz), 6.54 (1H, dt,J=8.2, 2.4 Hz), 5.29 (2H, s), 4.36 (2H, d, J=6.7 Hz), 3.97–4.05 (4H, m),1.61 (6H, s).

N-(4-Fluoro-2-(2-oxopiperidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazin-4(9H)-one.To intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid, (80 mg, 0.242 mmol) in CH₃CN/dimethylformamide (5 mL: 1 mL:) wasadded intermediate 125,1-(2-(aminomethyl)-5-fluorophenyl)piperidin-2-one hydrochloride salt,(69 mg, 0.266 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP) (139 mg, 0.266 mmol) anddiisopropylethylamine (169 μL, 0.968 mmol). The reaction mixture wasstirred at 23° C. for 3 h. The solvents were then removed in vacuo andan aqueous solution of HCl (1N, 25 mL) was added. This was extractedwith ethyl acetate (3×25 mL). The combined organic fractions were dried(MgSO₄), filtered and concentrated in vacuo. The crude material waspurified on a Biotage system using a silica gel column withHexanes/ethyl acetate (1:1) to (1:5) as eluent to afford 114 mg (88%yield) of the title compound. ¹HNMR 400 MHz (DMSO) δ ppm: 8.73 (1H, dd,(t), J=6.0 Hz), 7.46 (2H, m), 7.35 (4H, m), 7.18 (1H, dd, J=9.8, 3.0 Hz)7.0 (1H, m), 5.10 (2H, s), 4.43 (1H, dd, J=15.0, 7.08 Hz), 4.06 (1H, dd,J=15.0, 5.56), 4.02 (2H, t, J=5.0 Hz), 3.90 (2H, t, J=5.0 Hz), 3.64 (1H,m), 3.44 (1H, m), 2.45 (1H, m), 2.35 (1H, m), 1.86 (4H, m), 1.56 (6H,s). LCMS (M+H)⁺ m/z 535.

N-(4-Fluoro-2-(2-oxoazetidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid, (0.142 g, 0.430 mmol) in CH₃CN: dimethylformamide (30 mL: 5 mL)was added intermediate 120,1-(2-(aminomethyl)-5-fluorophenyl)azetidin-2-one hydrochloride, (0.100g, 0.43 mmol), (benzotriazole-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (0.207 g, 0.470 mmol) and diisopropylethylamine (280μL, 1.72 mmol). The reaction mixture was stirred at 23° C. for 18 h. Thesolvents were removed in vacuo and 1N HCl (50 mL) added. This wasextracted with ethyl acetate (2×50 mL). The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified on a Biotage system using a silica gel column with ethylacetate as eluent to afford the title compound (0.157 g, 72% yield). ¹HNMR (400 MHz, MeOD) δ ppm: 7.88 (1H, d, J=8.3 Hz), 7.76 (1H, d, J=8.0Hz), 7.58–7.30 (4H, m), 7.10 (1H, dd, J=10.2, 2.5 Hz), 6.90 (1H, m),5.20 (2H, s), 4.55 (2H, s), 4.04 (2H, m), 3.96 (2H, m), 3.78 (2H, t,J=4.2 Hz), 3.10 (2H, t, J=4.2 Hz), 1.58 (6H, s); LCMS (M+H)⁺ m/z 506.

N-(Benzo[b]thiophen-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid (0.200 g, 0.60 mmol) in CH₃CN:dimethylformamide (30 mL: 5 mL) wasadded intermediate 139, benzo[b]thiophen-7-ylmethanamine hydrochloride(0.069 g, 0.266 mmol),benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP) (0.347 g, 0.670 mmol) and diisopropylethylamine (420 μL, 2.40mmol). The reaction mixture was stirred at 23° C. for 60 h. The solventswere then removed in vacuo and 1N HCl (50 mL) added. This was extractedwith ethyl acetate (2×50 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified ona Biotage system using a silica gel column with hexane:ethyl acetate(1:1) to (1:5) gradient as eluent to afford the title compound (0.279 g,87% yield): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.11 (1H, dd, J=5.6 Hz), 7.81(1H, m), 7.77 (1H, d, J=5.6 Hz), 7.52 (1H, d, J=5.6 Hz), 7.48–7.26 (6H,m), 5.09 (2H, s), 4.67 (2H, d, J=5.2 Hz), 4.04 (2H, m), 3.90 (2H, m),1.58 (6H, s). LCMS (M+H)⁺ m/z 476.

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide.A solution of intermediate 35,3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylicacid in anhydrous dimethylformamide (4 mL) was treated with HATU (0.278g, 0.70 mmol) and stirred for 10 minutes. The reaction mixture wastreated with 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroaceticacid salt (0.24 g, 0.8 mmol), followed by dimethylaminopyridine (0.121g, 0.97 mmol), then stirred for 4 hours at 60° C. Following this, thesolvent was removed in vacuo and the remaining residue dissolved inethyl acetate (15 mL) and washed with 1.0 N HCl (15 mL). The organiclayer was dried (sodium sulfate), filtered, and concentrated to dryness.The crude product was purified by flash column chromatography (SiO₂),eluting with ethyl acetate. Fractions containing the product werepooled, concentrated to dryness and triturated with ether to provide0.366 g of the title compound as a white glassy solid. ¹H NMR (500 MHz,d₆-acetone) δ ppm: 8.71–8.82 (1H, m), 7.84–7.95 (1H, br), 7.47–7.62 (4H,m), 7.27–7.40 (5H, m), 7.20 (1H, dt, J=8.5, 2.7 Hz), 5.15–5.21 (2H, brs), 4.48–4.60 (4H, m), 2.96 (2H, s), 2.94 (2H, s), 1.62–1.64 (6H, s).

Intermediates 149–174

Intermediates 149–174 were prepared according to the coupling proceduresdescribed for intermediates 140–148.

N-(4-Fluorobenzyl)-3-(benzyloxy)-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 16,3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid and 4-fluorobenzylamine. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.67 (3H,d, J=6.6 Hz, CH₃), 3.91 (2H, m, CH₂), 4.12–4.35 (2H, m, CH₂), 4.52 (2H,d, J=5.9 Hz, NCH₂), 4.70 (1H, q, J=6.6 Hz, OCH), 5.33 (2H, s, OCH₂),7.02 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.35 (3H, m,aromatics), 7.47 (2H, m, aromatics), 7.71 (1H, broad t, NH).

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 7,3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide.White crystals; mp 189–190° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 3.01 (3H, d, J=4.5 Hz, NCH₃), 4.00 (2H, m, CH₂), 4.08 (1H, m,CH), 4.50 (2H, d, J=6.6 Hz, NCH₂), 4.71 (2H, s, OCH₂), 5.38 (2H, s,OCH₂), 6.88 (1H, broad q, NH), 7.07 (1H, m, aromatic), 7.16 (1H, dd,J=2.5 Hz and J=8.6 Hz, aromatic), 7.30–7.44 (6H, m, aromatics), 8.55(1H, broad t, NH). Anal. Calcd for C₂₄H₂₃FN₄O₅: C, 61.80; H, 4.97; N,12.01. Found: C, 61.84; H, 4.82; N, 12.00.

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid which was synthesized using the method described for the synthesisor intermediates 7 and 16, and intermediate 69,(4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine. White needles; mp155–157° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.03 (3H, t,J=7.5 Hz, CH₃), 1.97–2.02 (1H, m, CH), 2.29–2.32 (1H, m, CH), 3.83–3.88(2H, m, CH₂), 4.15–4.31 (2H, m, CH₂), 4.44 (2H, m, CH₂), 4.53 (1H, m,CH), 5.34 (2H, s, OCH₂), 7.08 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic),7.20 (1H, m, aromatic), 7.29–7.31 (3H, m, aromatics), 7.47 (2H, m,aromatics), 7.74 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.02 (1H, s,CH), 8.41 (1H, s, CH), 8.55 (1H, broad t, NH). Anal. Calcd forC₂₆H₂₅FN₆O₄: C, 61.89; H, 4.99; N, 16.65. Found: C, 61.67; H, 5.13; N,16.61.

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 85,(4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. Whitecrystals; mp 203° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm):1.65 (6H, s, 2×CH₃), 2.50 (3H, s, CH₃), 4.03 (4H, m, 2×CH₂), 4.46 (2H,d, J=6.6 Hz, NCH₂), 5.31 (2H, s, OCH₂), 7.06 (1H, dd, J=3 Hz and J=8.6Hz, aromatic), 7.16 (1H, m, aromatic), 7.30–7.34 (3H, m, aromatics),7.50 (2H, m, aromatics), 7.74 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic),8.28 (1H, s, CH), 8.45 (1H, broad t, NH). Anal. Calcd for C₂₇H₂₇FN₆O₄:C, 62.54; H, 5.25; N, 16.21. Found: C, 62.48; H, 5.31; N, 16.29.

N-(2-Fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 87,(2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. Whitecrystals; mp 183–185° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm):1.65 (6H, s, 2×CH₃), 2.52 (3H, s, CH₃), 4.05 (4H, m, 2×CH₂), 4.64 (2H,d, J=6.1 Hz, NCH₂), 5.33 (2H, s, OCH₂), 7.29–7.55 (8H, m, aromatics),7.84 (1H, broad t, NH), 8.45 (1H, s, CH). Anal. Calcd for C₂₇H₂₇FN₆O₄:C, 62.54; H, 5.25; N, 16.21. Found: C, 62.41; H, 5.40; N, 16.23.

Methyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoate.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 38, methyl 2-(aminomethyl)-5-fluorobenzoate. ¹HNMR (CDCl₃, 500 MHz) δ ppm: 1.61 (6H, s, gem-Me), 3.88 (3H, s, OMe),3.97 (2H, t, J=5.5 Hz, CH₂), 4.02 (2H, t, J=5.5 Hz, CH₂), 4.73 (2H, d,J=6.7 Hz, NCH₂), 5.25 (2H, s, OCH₂), 7.19 (1H, dt, J=3, 8.5 Hz, Ar—H),7.27–7.31 (3H, m, Ar—Hs), 7.48–7.50 (2H, m, Ar—Hs), 7.61 (1H, dd, J=5.5,8.5 Hz, Ar—H), 7.66 (1H, dd, J=3, 9.5 Hz, Ar—H). LC/MS m/z 496 (M+H).

N-(2-(Cyclopropylcarbamoyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 40,2-(aminomethyl)-N-cyclopropyl-5-fluorobenzamide. LC/MS m/z 521 (M+H).

N-(4-Fluoro-2-(morpholine-4-carbonyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 44,(2-(aminomethyl)-5-fluorophenyl)(morpholino)methanone. ¹H NMR (CDCl₃,500 MHz) δ ppm: 1.59 (6H, s), 3.29 (2H, brs), 3.57 (2H, m), 3.74 (4H,s), 3.98 (4H, m), 5.26 (2H, s), 6.88 (1H, dd, 3=8.2, 2.7 Hz), 7.03 (1H,dt, J=8.5, 2.5 Hz), 7.24–7.33 (3H, m), 7.42 (2H, dd, J=8.6, 5.3 Hz),7.47 (2H, dd, J=7.5, 2.0 Hz), 8.18 (1H, t, J=6.4 Hz); LC/MS m/z 551(M+H).

N-(4-Fluoro-2-(2-morpholino-2-oxoethoxy)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 131,2-(2-(aminomethyl)-5-fluorophenoxy)-1-morpholinoethanone. ¹H NMR (CDCl₃,500 MHz) δ ppm: 1.59 (6H, s, gem-Me), 3.38, 3.54 (4H, br, NCH₂), 3.62(4H, m, OCH₂), 3.96 (2H, m, NCH₂), 4.01 (2H, m, OCH₂), 4.55 (2H, s,OCH₂), 4.55 (2H, d, J=4.3 Hz, NCH₂), 5.17 (2H, s, OCH₂), 6.53 (1H, dd,J=10, 2.1 Hz, Ar—H), 6.63 (1H, dt, J=2.5, 8 Hz, Ar—H), 7.23–7.26 (1H, m,Ar—H), 7.28–7.30 (3H, m, Ar—Hs), 7.42–7.44 (2H, m, Ar—Hs), 8.00 (1H, t,J=5.5 Hz, NH); ¹³C NMR (CDCl₃, 125.77 Hz) δ ppm: 27.74, 38.76, 42.30,42.98, 45.38, 58.06, 66.55, 66.78, 66.91, 74.72, 76.27, 100.40, 100.61,108.07, 108.23, 122.56, 128.37, 128.49, 128.84, 130.88, 130.96, 139.69,141.36, 141.98, 156.70, 157.02, 157.10, 159.58, 162.04, 163.99, 162.86,165.79. HRMS (ESI) calcd for C₃₀H₃₄N₄O₇F (M+H) 581.2412. found 581.2393.

Dimethyl-carbamic acid2-{[(3-benzyloxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-pyrimido[2,1-c][1,4]oxazine-2-carbonyl)-amino]-methyl}-5-fluoro-phenylester. The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 133, 2-(aminomethyl)-5-fluorophenyldimethylcarbamate. ¹H NMR (CDCl₃, 500 MHz) δ ppm: 1.58 (6H, s, gem-Me),2.92, 3.05 (2s, NMe), 3.96 (2H, m, NCH₂), 4.00 (2H, m, OCH₂), 4.48 (2H,d, J=5.5 Hz, NCH₂), 5.26 (2H, s, OCH₂), 6.84 (1H, dd, J=2.5 Hz, 9 Hz,Ar—H), 6.87 (1H, dt, J=2.5 Hz, 8 Hz, Ar—H), 7.25–7.33 (4H, m, Ar—Hs),7.53 (2H, d, J=˜7 Hz, Ar—Hs), 7.78 (1H, brt, J=5 Hz, NH); ¹³C NMR(CDCl₃, 125.77 Hz) δ ppm: 27.68, 36.61, 36.89, 37.97, 42.97, 58.06,74.73, 76.23, 110.58, 110.77, 113.06, 113.23, 126.55, 126.58, 128.31,128.45, 128.91, 131.23, 131.31, 136.76, 140.70, 142.00, 150.60, 150.69,154.50, 156.30, 159.79, 161.40, 163.37, 162.43. HRMS (ESI) calcd forC₂₇H₃₀N₄O₆F (M+H) 525.2149. found 525.2163.

N-(4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 1-(2-(aminomethyl)-5-fluorophenyl)pyrrolidin-2-one, derivedfrom reduction of intermediate 111,4-fluoro-2-(2-oxopyrrolidin-1-yl)benzonitrile. ¹HNMR 400 MHz (MeOD) δppm: 7.44 (3H, m), 7.33 (3H, m), 7.11 (1H, dd, J=9.2, 3.0 Hz) 7.03 (1H,m), 5.21 (2H, s), 4.43 (2H, s), 4.08 (2H, t, J=5.0 Hz), 3.98 (2H, t,J=5.0 Hz), 3.85 (2H, t, J=7.1 Hz), 2.58 (2H, t, J=8.0 Hz), 2.23 (2H, m),1.61 (6H, s). LCMS (M+H)⁺ m/z 521.

N-(4-Fluoro-2-(2-oxoazepan-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2carboxamide. The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 1-(2-(aminomethyl)-5-fluorophenyl)azepan-2-one, derived fromreduction of intermediate 113,4-fluoro-2-(2-oxoazepan-1-yl)benzonitrile. ¹HNMR 400 MHz (DMSO) δ ppm:8.80 (1H, dd, (t), J=6.0 Hz), 7.46 (2H, m), 7.36 (4H, m), 7.08 (1H, dd,J=9.8, 2.8 Hz), 7.0 (1H, m), 5.09 (2H, s), 4.43 (1H, dd, J=15.2, 7.1Hz), 4.06 (1H, dd, J=15.2, 5.0 Hz), 4.02 (2H, t, J=5.0 Hz), 3.90 (2H, t,J=5.0 Hz), 3.77 (1H, m), 3.51 (1H, m), 2.70 (1H, m), 2.51 (2H, m), 1.76(6H, m), 1.56 (6H, s). LCMS (M+H)⁺ m/z 549.

N-(2-(2-Oxooxazolidin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 3-(2-(aminomethyl)phenyl)oxazolidin-2-one, derived fromreduction of intermediate 116, 2-(2-oxooxazolidin-3-yl)benzonitrile. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 8.90 (1H, t, J=6.0 Hz), 7.58–7.32 (7H, m),7.22 (2H, t, J=7.5 Hz), 5.08 (2H, s), 4.48 (2H, t, J=7.8 Hz), 4.44 (2H,d, J=6.0 Hz), 4.06–3.97 (4H, m), 3.88 (2H, m), 1.56 (6H, s); LCMS (M+H)⁺m/z 505.

N-(2-(2-Oxoazetidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 1-(2-(aminomethyl)phenyl)azetidin-2-one, derived from reductionof intermediate 115, 2-(2-oxoazetidin-1-yl)benzonitrile. ¹H NMR (400MHz, CDCl₃) δ ppm: 8.67 (1H, brt, J=6.3 Hz), 7.60 (1H, dd, J=1.3, 7.6Hz), 7.53–7.50 (1H, dd, m), 7.34–7.24 (5H, m), 7.18 (1H, ddd(dt), J=1.2,7.4 Hz), 7.10 (1H, dd, J=1.2, 8.0 Hz), 5.27 (2H, s), 4.60 (2H, d, J=6.3Hz), 4.01–3.95 (4H, m), 3.71 (2H, t, J=4.5 Hz), 3.10 (2H, t, J=4.5 Hz),1.60 (6H, s); LCMS (⁺ESI, M+H⁺) m/z 489.

N-(4-Fluoro-2-(thiazol-2-ylamino)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and N-(2-(aminomethyl)-5-fluorophenyl)thiazol-2-amine, derived fromreduction of intermediate 123,4-fluoro-2-(thiazol-2-ylamino)benzonitrile. ¹H NMR (400 MHz, DMSO-d6) δppm: 9.92 (1H, s), 9.10 (1H, t, J=6.3 Hz), 8.19 (1H, dd, J=2.8, 12.3Hz), 7.41–7.38 (2H, m), 7.32–7.28 (5H, m), 6.99 (1H, d, J=3.8 Hz), 6.71(1H, ddd(dt), J=2.8, 8.3), 5.05 (2H, s), 4.45 (2H, d, J=6.3 Hz),4.01–3.98 (2H, m), 3.88–3.85 (2H, m), 1.54 (6H, s) LCMS (⁺ESI, M+H⁺) m/z536.

N-(4-Fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid andN-(2-(aminomethyl)-5-fluorophenyl)-5-methyl-1,3,4-thiadiazol-2-amine,derived from reduction of intermediate 124,4-fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzonitrile. LCMS(⁺ESI, M+H⁺) m/z 551.

N-(4-Fluoro-2-(2-oxooxazolidin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 3-(2-(aminomethyl)-5-fluorophenyl)oxazolidin-2-one, derivedfrom reduction of intermediate 117,4-fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile. ¹H NMR (400 MHz, MeOD) δppm: 9.48 (1H, dd, J=8.6, 6.5 Hz), 7.41 (2H, m), 7.32 (3H, m), 7.22 (1H,dd, J=9.6, 2.5 Hz), 7.08 (1H, td, J=8.6, 2.7 Hz), 5.21 (2H, s), 4.57(2H, t, J=7.7 Hz), 4.50 (2H, s), 4.07 (4H, m), 3.99 (2H, m), 1:61 (6H,s). LCMS (M+H)⁺ m/z 523.

(R)-N-(2-(2-((tert-Butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and(S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one,derived from reduction of intermediate 122,(R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile¹HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.47 (2H, m), 7.35 (4H,m), 7.00 (1H, broad s), 5.09 (2H, s), 4.60–4.10 (3H, m), 4.02 (3H, m),3.88 (2H, m), 3.53 (2H, broad s), 2.42–2.35 (2H, m), 1.94 (1H, m), 1.56(3H, s), 1.55 (3H, s), 0.82 (9H, broad s), −0.01 (6H, s). LCMS (M+H)⁺m/z 665.

(S)-N-(2-(2-((tert-Butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and(S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one,derived from reduction of intermediate 121,(R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile.¹HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.52–7.33 (7H, m), 7.02(1H, broad s), 5.60 (2H, s), 4.60–4.20 (2H, m), 4.02 (3H, t, J=5.0 Hz),3.89 (3H, t, 5.0 Hz), 3.53 (2H, broad s), 2.51 (2H, s), 2.44–2.26 (2H,m), 1.94 (1H, broad s), 1.57 (3H, s), 1.55 (3H, s), 0.82 (9H, broad s),−0.02 (6H, s). LCMS (M+H)⁺ m/z 665.

N-(4-Fluoro-2-(N-methylacetamido)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid N-(2-(aminomethyl)-5-fluorophenyl)-N-methylacetamide, derived fromreduction of intermediate 114,N-(2-cyano-5-fluorophenyl)-N-methylacetamide. ¹HNMR 400 MHz (MeOD) δppm: 7.49–7.33 (6H, m), 7.15–7.06 (2H, m), 5.22 (2H, s), 4.41 (2H, d,J=2.4 Hz), 4.09 (2H, t, J=5.1 Hz), 4.01 (2H, t, J=5.1 Hz), 3.25 (0.4H,s), 3.22 (2.6H, s), 1.85 (3H, s), 1.63 (6H, s). LCMS (M+H)⁺ m/z 509.

N-(2-Amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid 2-(aminomethyl)-5-fluorobenzenamine. ¹HNMR 400 MHz (MeOD) δ ppm:¹HNMR 400 MHz (MeOD) δ ppm: 7.36 (2H, m), 7.30 (3H, m), 7.10 (1H, dd,J=8.3, 6.5 Hz), 6.47 (1H, dd, J=11.1, 2.5 Hz), 6.32 (1H, ddd, (dt),J=8.6, 2.5 Hz), 5.19 (2H, s), 4.40 (2H, s), 4.07 (2H, t, J=5.0 Hz), 3.99(2H, t, J=5.0 Hz), 1.61 (6H, s). LCMS (M+H)⁺ m/z 453.

N-(2-(Ethylamino)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 2-(aminomethyl)-N-ethyl-5-fluorobenzenamine. ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.27 (3H, t, J=7.1 Hz, CH₃), 1.63 (6H, s, 2×CH₃), 3.10(2H, q, J=7.1 Hz, CH₂), 4.04 (4H, m, 2×CH₂), 4.45 (2H, d, J=6.6 Hz,NCH₂), 5.27 (2H, s, OCH₂), 6.28 (1H, broad s, aromatic), 6.31 (1H, m,aromatic), 6.98 (1H, m, aromatic), 7.3–7.38 (3H, m, aromatics), 7.49(2H, m, aromatics), 7.54 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₆H₃₀FN₄O₄ [M+H⁺]: 481.2251. found: 481.2254.

N-(4-Fluorobenzyl)-3-(benzyloxy)-N-methoxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and (4-fluorophenyl)-N-methoxymethanamine. White crystals; mp 141°C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.66 (6H, s,2×CH₃), 3.59 (3H, s, OCH₃), 4.07 (4H, m, 2×CH₂), 4.90 (2H, s, NCH₂),5.20 (2H, s, OCH₂), 6.81 (2H, m, aromatics), 7.26–7.30 (3H, m,aromatics), 7.36 (2H, m, aromatics), 7.44 (2H, m, aromatics). HRMS(ESI⁺) calculated for C₂₅H₂₇FN₃O₅ [M+H⁺]: 468.1935. found: 468.1916.

N-(4-Fluoro-2-(1,2,3-thiadiazol-4-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and (4-fluoro-2-(1,2,3-thiadiazol-4-yl)phenyl)methanamine. ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.66 (6H, s, 2×CH₃), 4.02 (4H, m, 2×CH₂), 4.57(2H, d, J=6.6 Hz, NCH₂), 5.32 (2H, s, OCH₂), 7.18 (1H, m, aromatic),7.27–7.34 (4H, m, aromatics), 7.54 (2H, m, aromatics), 7.74 (1H, dd,J=6.2 Hz and J=8.6 Hz, aromatic), 8.71 (1H, s, CH), 8.80 (1H, broad t,NH). HRMS (ESI⁺) calculated for C₂₆H₂₅FN₅O₄S [M+H⁺]: 522.1611. found:522.1601.

N-(4-Fluoro-2-(5-methyloxazol-2-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and (4-fluoro-2-(5-methyloxazol-2-yl)phenyl)methanamine. Whitecrystals; mp 186° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.61 (6H, s, 2×CH₃), 2.43 (3H, s, CH₃), 4.02 (4H, m, 2×CH₂), 4.80(2H, d, J=6.3 Hz, NCH₂), 5.25 (2H, s, OCH₂), 6.82 (1H, s, CH), 7.11 (1H,m, aromatic), 7.29–7.34 (3H, m, aromatics), 7.52 (2H, m, aromatics),7.65 (1H, dd, J=2.5 Hz and J=9.6 Hz, aromatic), 7.69 (1H, dd, J=6.1 Hzand J=8.6 Hz, aromatic), 9.32 (1H, broad t, NH). HRMS (ESI⁺) calculatedfor C₂₈H₂₈FN₄O₅ [M+H⁺]: 519.2044. found: 519.2024.

N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and (4-fluoro-2-iodophenyl)methanamine. White solid. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.66 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂, ), 4.57 (2H, d,J=6.6 Hz, NCH₂), 7.05 (1H, m, aromatic), 7.3–7.38 (3H, m, aromatics),7.42 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.53 (2H, m, aromatics),7.56 (1H, dd, J=2.6 Hz and J=8.0 Hz, aromatic), 8.05 (1H, broad t, NH).HRMS (ESI⁺) calculated for C₂₄H₂₄FIN₃O₄ [M+H⁺]: 564.0796. found:564.0809.

N-(4-Fluoro-2-(2-methoxypyridin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.Intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.350 g, 0.62 mmol) in a mixture of acetonitrile (12 ml) and water (12ml) was treated with 2-methoxypyridin-3-ylboronic acid (0.190 g, 1.24mmol), sodium carbonate (0.20 g, 1.88 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.15 g). The reaction mixturewas degassed, flushed with argon and heated at 90° C. for 30 min. Thereaction mixture was then diluted with ethyl acetate, washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated.Chromatography of the residue on silica gel (elution gradient of ethylacetate in hexane) gave 0.245 g (72% yield) of the title material as awhite solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 3.89 (3H,s, OCH₃), 4.04 (4H, m, 2×CH₂), 4.37 (2H, broad, NCH₂), 5.26 (2H, s,OCH₂), 6.93 (1H,dd, J=2.5 Hz and J=9 Hz, aromatic), 7.0 (1H,dd, J=5 Hzand J=7 Hz, aromatic), 7.06 (1H, m, aromatic), 7.3–7.5 (8H, m, aromaticsand NH), 8.24 (1H, m, aromatic). HRMS (ESI⁺) calculated for C₃₀H₃₀FN₄O₅[M+H⁺]: 545.2200. found: 545.2184.

N-(4-Fluoro-2-phenyl-benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.Intermediate 174,N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.266 mmol) in a mixture of acetonitrile (10 ml) and water (10ml) was treated with phenylboronic acid (0.042 g, 0.35 mmol), sodiumcarbonate (0.062 g, 0.58 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.070 g). The reaction mixturewas degassed, flushed with argon and heated at 90° C. for 30 min. Thereaction mixture was then diluted with ethyl acetate, washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated.Chromatography of the residue on silica gel (elution gradient of ethylacetate in hexane) gave 0.124 g (91% yield) of the title material as alight yellow solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.61 (6H, s, 2×CH₃),4.03 (4H, m, 2×CH₂), 4.49 (2H, d, J=6.1 Hz, NCH₂), 7.02 (2H, m,aromatics), 7.29–7.51 (12H, m, aromatics and NH). HRMS (ESI⁺) calculatedfor C₃₀H₂₉FN₃O₄ [M+H⁺]: 514.2142. found: 514.2137.

N-(4-Fluoro-2-(1H-pyrazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.Intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.27 mmol) was reacted with 1H-pyrazol-5-ylboronic acid (0.060g, 0.54 mmol), sodium carbonate (0.085 g, 0.81 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.070 g) to give 0.085 g (62%yield) of the title material as a white solid after chromatography onsilica gel. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.63 (6H, s, 2×CH₃), 4.03(4H, m, 2×CH₂), 4.65 (2H, d, J=6.5 Hz, NCH₂), 5.25 (2H, s, OCH₂), 6.54(1H, d, J=2.5 Hz, CH), 7.03 (1H, m, aromatic), 7.25 (1H, dd, J=2.5 Hzand J=9.8 Hz, aromatic), 7.35 (3H, m, aromatics), 7.53 (2H, m,aromatics), 7.56 (1H, d, J=2.5 Hz, CH), 7.60 (1H, dd, J=6.1 Hz and J=8.6Hz, aromatic), 8.96 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₇H₂₇FN₅O₄ [M+H⁺]: 504.2047. found: 504.2068.

N-(4-Fluoro-2-(2-(trimethylsilyl)ethynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.277 g, 0.49 mmol) in a mixture of N,N-dimethylformamide (3 ml) andpiperidine (1.2 ml) was treated under argon withdichlorobis(triphenylphosphine)palladium(II) (0.020 g),triphenylphosphine (0.010 g), copper(I) iodide (0.010 g) followed by(trimethylsilyl)acetylene (0.21 ml, 1.47 mmol). The resulting mixturewas sealed and heated at 50° C. for one hour. The reaction mixture wasthen diluted with ethyl acetate, washed with water and brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure.Chromatography of the residue on silica gel (elution gradient of ethylacetate in hexane) gave 0.164 g (63% yield) of the title material as alight yellow solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 0.27 (9H, s, SiCH₃),1.64 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂), 4.71 (2H, d, J=6.1 Hz, NCH₂),5.32 (2H, s, OCH₂), 6.99 (1H, m, aromatic), 7.19 (1H,dd, J=2.6 Hz andJ=9.1 Hz, aromatic), 7.3–7.37 (4H, m, aromatics), 7.48–7.51 (2H, m,aromatics), 7.75 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₉H₃₃FN₃O₄Si [M+H⁺]: 534.2224. found: 534.2229.

N-(2-Ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 178,N-(4-fluoro-2-(2-(trimethylsilyl)ethynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.28 mmol) in methanol (5 ml) was treated with potassiumcarbonate (0.120 g, 0.84 mmol) and the resulting mixture stirred at 22°C. for one hour. The reaction mixture was then diluted with ethylacetate, washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give 0.129 g (100%yield) of the title material as a light yellow solid. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.64 (6H, s, 2×CH₃), 3.31 (1H, s, CH), 4.04 (4H, m,2×CH₂), 4.69 (2H, d, J=6.6 Hz, NCH₂), 5.31 (2H, s, OCH₂), 7.04 (1H, m,aromatic), 7.21 (1H,dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.32–7.42 (3H,m, aromatics), 7.40 (1H,dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.52–7.54(2H, m, aromatics), 8.00 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₆H₂₅FN₃O₄ [M+H]: 462.1829. found: 462.1822.

N-(4-Fluoro-2-(3-methylisoxazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 179,N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.32 mmol) in dimethyl sulfoxide (5 ml) was treated withnitromethane (0.14 ml, 1.92 mmol),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM) (0.241 g, 1.0 mmol) (M. Kunishima et al., Tetrahedron, 55, 1999,13159–13170) and 4-(dimethylamino)pyridine (DMAP) (0.010 g) and theresulting mixture stirred at 22° C. for 16 h. Identical quantities ofnitromethane, DMTMM and DMAP were then added and the mixture was stirredfor another 24 h. The reaction mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate and brine, then dried overanhydrous magnesium sulfate and concentrated under reduced pressure.Chromatography of the residue on silica gel (elution gradient of ethylacetate in dichloromethane) gave 0.122 g (73% yield) of the titlematerial as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.62 (6H, s,2×CH₃), 2.39 (3H, s, CH₃), 4.04 (4H, m, 2×CH₂), 4.69 (2H, d, J=6.1 Hz,NCH₂), 5.31 (2H, s, OCH₂), 6.36 (1H, m, CH), 7.13 (1H, m, aromatic),7.30–7.35 (4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.58 (1H,dd,J=5.5 Hz and J=8.6 Hz, aromatic), 8.06 (1H, broad t, NH). HRMS (ESI⁺)calculated for C₂₈H₂₈FN₄O₅ [M+H⁺]: 519.2044. found: 519.2059.

N-(2-(3-Bromoisoxazol-5-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 179,N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.350 g, 0.76 mmol) in a mixture of ethyl acetate (10 ml) and water (2ml) was treated with potassium bicarbonate (0.230 g, 2.3 mmol) followedby dibromoformaldoxime (0.354 g, 1.75 mmol) (D. M. Vyas, Y. Chiang andT. W. Doyle, Tetrahedron Letters, 1984, 25, 487–490) and the resultingmixture stirred at 22° C. After 1 h, identical quantities of potassiumbicarbonate and dibromoformaldoxime were added and the mixture stirredfor another 1.5 h. The reaction mixture was then diluted with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Crystallization of the residue fromether gave 0.300 g (68% yield) of the title material as a white solid.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂),4.67 (2H, d, J=6.6 Hz, NCH₂), 5.32 (2H, s, OCH₂), 6.60 (1H, s, CH), 7.17(1H, m, aromatic), 7.30–7.36 (4H, m, aromatics), 7.51–7.53 (2H, m,aromatics), 7.60 (1H,dd, J=5.5 Hz and J=8.6 Hz, aromatic), 8.01 (1H,broad t, NH). HRMS (ESI⁺) calculated for C₂₇H₂₅BrFN₄O₅ [M+H⁺]: 583.0992.found: 583.0986.

N-(4-Fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.Reaction of intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.563 g, 1.00 mmol) with propargyl alcohol (0.18 ml, 3.2 mmol) usingthe conditions described for intermediate 178 gave 0.415 g (85% yield)of the title material as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm:1.64 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂), 4.39 (2H, d, J=6.6 Hz, CH₂),4.68 (2H, d, J=6.0 Hz, CH₂), 5.29 (2H, s, OCH₂), 6.99 (1H, m, aromatic),7.13 (1H,dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.22 (1H,dd, J=5.6 Hz andJ=8.6 Hz, aromatic), 7.33–7.37 (3H, m, aromatics), 7.44–7.47 (2H, m,aromatics), 7.68 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₇H₂₇FN₃O₅ [M+H⁺]: 492.1935. found: 492.1939.

3-[2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynylmethanesulfonate. A solution of intermediate 182,N-(4-fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.280 g, 0.57 mmol) and triethylamine (0.12 ml, 0.86 mmol) indichloromethane (5 ml) was cooled to 0° C., treated drop wise withmethanesulfonyl chloride (0.050 ml, 0.64 mmol) and then stirred for 30min. The reaction mixture was then diluted with ethyl acetate, washedwith saturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. Chromatography of theresidue on silica gel (elution gradient of ethyl acetate in hexane) gave0.245 g (75% yield) of the title material as a white solid. ¹HNMR 400MHz (CDCl₃) δ ppm: 1.65 (6H, s, 2×CH₃), 3.10 (3H, s, SCH₃), 4.05 (4H, m,2×CH₂), 4.67 (2H, d, J=6.1 Hz, NCH₂), 5.03 (2H, s, CH₂), 5.29 (2H, s,OCH₂), 7.07 (1H, m, aromatic), 7.18 (1H,dd, J=2.5 Hz and J=9.1 Hz,aromatic), 7.32–7.36 (3H, m, aromatics), 7.38 (1H,dd, J=5.5 Hz and J=8.6Hz, aromatic), 7.49–7.51 (2H, m, aromatics), 7.77 (1H, broad t, NH). MS(ESI⁺) m/e 570 [M+H⁺].

N-(2-(3-(Dimethylamino)prop-1-ynyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 183,3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynylmethanesulfonate (0.100 g, 0.18 mmol) in acetonitrile (5 ml) was treatedat 22° C. with 0.3 ml (0.6 mmol) of a 2 M solution of dimethylamine intetrahydrofuran and the resulting mixture was stirred for 30 min. Thereaction mixture was then diluted with ethyl acetate, washed withsaturated sodium bicarbonate, brine, then dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give 0.080 g (88%yield) of the title material as a white solid. ¹HNMR 400 MHz (CDCl₃) δppm: 1.64 (6H, s, 2×CH₃), 2.43 (6H, s, 2×NCH₃), 3.58 (2H, broad s, CH₂),4.05 (4H, m, 2×CH₂), 4.70 (2H, d, J=6.0 Hz, NCH₂), 5.30 (2H, s, OCH₂),7.01 (1H, m, aromatic), 7.18 (1H,dd, J=3 Hz and J=9.1 Hz, aromatic),7.32–7.38 (4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.79 (1H,broad t, NH). HRMS (ESI⁺) calculated for C₂₉H₃₂FN₄O₄ [M+H⁺]: 519.2408.found: 519.2407.

N-(4-Fluoro-2-(3-(methylthio)prop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 183,3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynylmethanesulfonate (0.160 g, 0.28 mmol) in N,N-dimethylformamide (3 ml)was treated at 0° C. with sodium thiomethoxide (0.026 g, 0.37 mmol) andthe resulting mixture stirred for 2 h. The reaction mixture was thendiluted with ethyl acetate, washed with saturated sodium bicarbonate andbrine, then dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. Chromatography of the residue on silica gel(elution gradient of ethyl acetate in hexane) gave 0.114 g (78% yield)of the title material as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm:1.64 (6H, s, 2×CH₃), 2.28 (3H, s, SCH₃), 3.45 (2H, s, SCH₂), 4.05 (4H,m, 2×CH₂), 4.69 (2H, d, J=6.1 Hz, NCH₂), 5.31 (2H, s, OCH₂), 6.98 (1H,m, aromatic), 7.15 (1H,dd, J=3 Hz and J=9.1 Hz, aromatic), 7.32–7.38(4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.80 (1H, broad t,NH). HRMS (ESI⁺) calculated for C₂₈H₂₉FN₃O₄S [M+H⁺]: 522.1863. found:522.1844.

N-(4-Fluoro-2-(3-(methylsulfonyl)prop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 185,N-(4-fluoro-2-(3-(methylthio)prop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.110 g, 0.21 mmol) in dichloromethane (3 ml) was treated at 0° C. with3-chloroperoxybenzoic acid (0.120 g of 85%, 0.59 mmol) and the resultingmixture was stirred at 22° C. for 30 min. The reaction mixture was thendiluted with ethyl acetate, washed with saturated sodium bicarbonate,brine, then dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. Chromatography of the residue on silica gel(elution gradient of ethyl acetate in dichloromethane) gave 0.074 g (64%yield) of the title material as a white solid. ¹HNMR 400 MHz (CDCl₃) δppm: 1.64 (6H, s, 2×CH₃), 3.03 (3H, s, SCH₃), 4.03 (2H, s, SCH₂), 4.05(4H, m, 2×CH₂), 4.65 (2H, d, J=6.0 Hz, NCH₂), 5.27 (2H, s, OCH₂), 7.06(1H, m, aromatic), 7.17 (1H,dd, J=3 Hz and J=8.6 Hz, aromatic),7.31–7.38 (6H, m, aromatics), 8.12 (1H, broad t, NH). HRMS (ESI⁺)calculated for C₂₈H₂₉FN₃O₆S [M+H⁺]: 554.1761. found: 554.1784.

Diethyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.A solution of intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.200 g, 0.35 mmol) and triphenylphosphine (0.020 mg) in ethanol (5 ml)was flushed with argon and then treated with N,N-diisopropylethylamine(0.25 ml, 1.4 mmol), palladium(11) acetate (0.020 g) and diethylphosphite (0.15 ml, 1.16 mmol). The reaction mixture was then sealed andheated at 80° C. for 18 h. The reaction mixture was then diluted withethyl acetate, washed with 0.1 N hydrochloric acid, saturated sodiumbicarbonate, brine, then dried over anhydrous magnesium sulfate andconcentrated. Chromatography of the residue on silica gel (elutiongradient of acetonitrile in dichloromethane) gave 0.103 g (51% yield) ofthe title compound as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.36(6H, t, J=6.6 Hz, 2×CH₃), 1.64 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂),4.08–4.22 (4H, m, 2×OCH₂), 4.78 (2H, d, J=6.6 Hz, NCH₂), 5.29 (2H, s,OCH₂), 7.21 (1H, m, aromatic), 7.29–7.34 (3H, m, aromatics), 7.45–7.52(3H, m, aromatics), 7.65–7.72 (1H, m, aromatic), 8.67 (1H, broad t, NH).HRMS (ESI⁺) calculated for C₂₈H₃₄FN₃O₇P [M+H⁺]: 574.2118. found:574.2126.

Ethyl hydrogen2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.A solution of intermediate 187, diethyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate(0.115 g, 0.20 mmol) in tetrahydrofuran (3 ml)/ethanol (3 mL) wastreated with 1 N aqueous sodium hydroxide (1.0 ml, 1.0 mmol) and theresulting mixture heated at 45° C. for 2 h. The reaction mixture wasthen diluted with ethyl acetate, washed with 0.1 N hydrochloric acid,brine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified on a Shimadzu automated preparative HPLC system(column YMC Pack C-18, 5μ, 20×250 mm, elution gradientacetonitrile-water 0.1% trifluoroacetic acid) to give 0.070 g (64%yield) of the title material as a clear oil. ¹HNMR 400 MHz (CDCl₃) δppm: 1.37 (3H, t, J=7.1 Hz, CH₃), 1.62 (6H, s, 2×CH₃), 4.04 (4H, m,2×CH₂), 4.18 (2H, m, OCH₂), 4.75 (2H, broad d, J=5 Hz, NCH₂), 5.32 (2H,s, OCH₂), 7.21 (1H, m, aromatic), 7.30–7.33 (3H, m, aromatics),7.38–7.40 (2H, m, aromatics), 7.47–7.52 (1H, m, aromatic), 7.56–7.63(1H, m, aromatic), 8.56 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₆H₃₀FN₃O₇P [M+H⁺]: 546.1805. found: 546.1786.

N-(2-Acetamido-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 169,N-(2-amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.033 g, 0.073 mmol) in dry tetrahydrofuran (10 mL) was added acetylchloride (5.7 μL, 0.08 mmol) and diisopropylethylamine (38 μL, 0.22mmol). The reaction mixture was stirred at 23° C. for 3 h. NaHCO₃ (0.25M, 20 mL) was then added and the organic material extracted with ethylacetate (3×25 mL). The organic extracts were combined, dried (MgSO₄) andconcentrated in vacuo. The residue was purified on a Biotage systemusing a silica gel column with ethyl acetate:Hex (1:2 to 2:1) as eluentto afford the title compound (0.025 g, 69% yield). ¹HNMR 400 MHz (MeOD)δ (ppm): 7.66 (1H, dd, J=10.5, 2.8 Hz), 7.43–7.25 (6H, m), 6.87 (1H,ddd, (dt), J=8.8, 2.6 Hz), 5.19 (2H, s), 4.47 (2H, m), 4.08 (2H, t,J=4.9 Hz), 3.99 (2H, t, J=4.9 Hz), 2.19 (3H, s), 1.62 (6H, s). LCMS(M+H)⁺ m/z 495.

2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoicacid. To a suspension of intermediate 154, methyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoate.(500 mg, 1.01 mmol) in MeOH (10 mL) and CH₃CN (5 mL) was added 1N NaOH(2 mL) and the mixture stirred at room temperature for 2 hrs. Themixture was concentrated in vacuo and the residue purified by reversephase column chromatography (YMC, C-18 ODS, 10–25% CH₃CN/H₂O) to provide90 mg (Yield 19%) of the title compound as an off-white powder: LC/MSm/z 482 (M+H).

N-(2-((2-Aminoethyl)carbamoyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A mixture of intermediate 190,2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoicacid, (59 mg, 0.12 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, HATU (76 mg, 0.2 mmol; Aldrich) in DMF (1 mL) wasstirred for 20 min. To this mixture was added ethanolamine (20 mg, 0.3mmol) and the stirring continued overnight. The mixture was concentratedin vacuo, dissolved in CH₂Cl₂, washed with water then dried (MgSO₄),filtered, and concentrated to provide 55 mg (Yield 87%) of the titlecompound: LC/MS m/z 525 (M+H).

(R)-N-(4-Fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a stirred solution of intermediate 166,(R)-N-(2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.10 g, 0.150 mmol) in tetrahydrofuran (5 mL) at 23° C. was added asolution of tetrabutylammonium fluoride (1M in tetrahydrofuran) (180 μL,0.18 mmol). The reaction mixture was stirred at 23° C. for 3 h. NaHCO₃(1N in H₂O, 30 mL) was then added and the organic material was extractedwith ethyl acetate (2×25 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified ona Biotage system using a silica gel column with ethyl acetate/Hexanes(1:1) to ethyl acetate 100% as eluent to afford the title compound(0.060 g, 73% yield): ¹HNMR 400 MHz (MeOD) δ (ppm): 7.55 (1H, dd, (t),6.6 Hz), 7.43 (2H, m), 7.13 (1H, dd, J=9.5, 2.4 Hz), 7.03 (1H, m), 5.26(2H, s), 4.57 (1H, m), 4.32 (2H, m), 4.08 (2H, t, J=5.0 Hz), 7.03 (2H,t, J=5.0 Hz), 3.53 (2H, m), 2.69–2.56 (2H, m), 2.38 (1H, m), 2.22 (1H,m), 1.62 (6H, s). LCMS (M+H)⁺ m/z 551.

(R)-(1-(2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methylacetate. To a solution of intermediate 192,(R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.045 g, 0.082 mmol) in tetrahydrofuran (5 mL) was added acetylchloride (12.8 μL, 0.180 mmol) and diisopropylethylamine (31.4 μL, 0.180mmol). The reaction mixture was stirred at 23° C. for 4 h. NaHCO₃ (1N inH₂O, 30 mL) was then added and the organic material was extracted withethyl acetate (2×25 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified ona Biotage system using a silica gel column with ethyl acetate/Hexanes(1:1) to ethyl acetate 100% as eluent to afford the title compound(0.032 g, 67% yield): ¹HNMR 400 MHz (MeOD) δ ppm: 7.48 (3H, m), 7.33(3H, m), 7.16 (1H, m), 7.03 (1H, m), 5.24 (2H, s), 4.60 (1H, m), 4.55(1H, m), 4.22 (1H, dd, J=12.0, 4.5 Hz), 4.08 (2H, t, J=5.0 Hz), 3.99(3H, m), 2.62 (2H, m), 2.44 (1H, m), 2.09–1.92 (5H, m), 1.62 (3H, s),1.61 (3H, s). LCMS (M+H)⁺ m/z 593.

(R)-(1-(2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methylmethanesulfonate. To a stirred solution of intermediate 192,(R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.160 g, 0.291 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added triethylamine(81 μL, 0.582 mmol) and methanesulfonyl chloride (27 μL, 0.349 mmol).The reaction mixture was stirred at 23° C. for 4 h. Water (50 mL) wasthen added and the organic material was extracted with CH₂Cl₂ (2×50 mL).The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo to afford the title compound (0.178 g, 98% yield).The crude material was used without further purification for the nextstep: LCMS (M+H)⁺ m/z 629.

(R)-N-(2-(2-(Azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 194,(R)-(1-(2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methylmethanesulfonate (0.150 g, 0.239 mmol) in DMF (10 mL) was added sodiumazide (0.019 g, 0.287 mmol). The resulting mixture was stirred at 50° C.for 6 h. Water (50 mL) was then added and the organic material wasextracted with ethyl acetate (2×50 mL). The combined organic extractswere washed with H₂O (50 mL), dried (MgSO₄), filtered and concentratedin vacuo to afford the title compound (0.125 g, 91% yield). LCMS (M+H)⁺m/z 576.

N-(Benzo[b]thiophen-1,1-dione-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 147,N-(benzo[b]thiophen-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.100 g, 0.21 mmol) in dichloroethane (10 mL) was added per-acetic acid(32% in H₂O) (1.0 mmol, 200 μL). The reaction mixture was stirred at 23°C. for 48 h. Water (50 mL) was added and the organic material wasextracted with CH₂Cl₂ (2×50 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo to afford the titlecompound (0.106 g, 99% yield): ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.11(1H,t, J=6.4 Hz), 7.65 (1H, d, J=6.8 Hz) 7.59–7.29 (9H, m), 5.15 (2H, s),4.77 (2H, d, J=6.5 Hz), 4.04 (2H, t, J=5.0 Hz), 3.90 (2H, m), 1.59 (6H,s). LCMS (M+H)⁺ m/z 508.

1-(Azidomethyl)-4-fluoro-2-iodobenzene. A solution of1-(bromomethyl)-4-fluoro-2-iodobenzene (M. Protiva et al., Collect.Czech. Chem. Comm., 44, 1979, 2108–2123) (17.9 g, 56.8 mmol) inN,N-dimethylformamide (35 ml) was treated with sodium azide (5.0 g, 76.7mmol) and the resulting mixture was heated to 50° C. for 4 h. The cooledmixture was filtered, the filtrate was concentrated in vacuo and theresidue was chromatographed on silica gel (elution hexane) to give 15.7g (97% yield) of the title azide as a clear oil. ¹HNMR 400 MHz (DMSO-d₆)δ (ppm): 4.53 (2H, s, CH₂), 7.32 (1H, m, aromatic), 7.54 (1H, dd, J=6 Hzand J=8.6 Hz, aromatic), 7.83 (1H, dd, J=3 Hz and J=8 Hz, aromatic).

(4-Fluoro-2-iodophenyl)methanamine. A solution of1-(azidomethyl)-4-fluoro-2-iodobenzene (15.2 g, 54.8 mmol) in DMF (35ml) at 0° C. was treated with triphenylphosphine (21.6 g, 81.2 mmol) andthen stirred for 1 h. The reaction mixture was then treated with water(5 ml) and heated at 55° C. for 1 h. The DMF was concentrated in vacuoand the residue was diluted with ethyl acetate (200 ml). The organicphase was extracted with 0.5 N hydrochloric acid (140 ml) and theaqueous extract was washed with ethyl acetate. The aqueous phase wasthen adjusted to pH 9 with 1 N LiOH and extracted with ethyl acetate(2×200 ml). The combined organic phases were dried over anhydrousmagnesium sulfate and concentrated. The residue was diluted with ether(200 ml), filtered and concentrated. Distillation of the residue invacuo gave 8.52 g (62% yield) of the title amine as a clear oil: bp 85°C./0.35 torr (bulb to bulb distillation air bath temperature). ¹HNMR 400MHz (DMSO-d₆) δ (ppm): 3.64 (2H, s, CH₂), 7.27 (1H, m, aromatic), 7.53(1H, dd, J=6 Hz and J=8.6H, aromatic), 7.83 (1H, dd, J=3 Hz and J=8 Hz,aromatic).

tert-Butyl 4-fluoro-2-iodobenzylcarbamate. A solution of(4-fluoro-2-iodophenyl)methanamine (21.4 g, 85.2 mmol) indichloromethane (350 ml) was treated at 0° C. with di-tert-butyldicarbonate (20.5 g, 93.8 mmol) followed by triethylamine added dropwise over 30 min. The resulting mixture was then allowed to warm up to25° C. and stirred for 18 h. The reaction mixture was then washed withwater, brine, dried over anhydrous magnesium and concentrated.Chromatography of the residue on silica gel (elution gradient of ethylacetate 5–20% in hexane) gave 28.37 g (95% yield) of the title carbamateas a clear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.47 (9H, s, t-Bu), 4.32(2H, d, J=6.0 Hz, NCH₂), 5.04 (1H, broad, NH), 7.07 (1H, m, aromatic),7.35 (1H, m, aromatic), 7.56 (1H, dd, J=2.8 Hz and J=8 Hz, aromatic).

tert-Butyl 2-(dimethoxyphosphoryl)-4-fluorobenzylcarbamate. A solutionof tert-butyl 4-fluoro-2-iodobenzylcarbamate (5.00 g, 14.24 mmol),dimethyl phosphite (4.70 g, 42.7 mmol) and N,N-diisopropylethylamine(9.9 ml, 56.8 mmol) in methanol (75 ml) was flushed with argon and thentreated with triphenylphosphine (0.5 g) and palladium(II) acetate (0.75g). The resulting mixture was then sealed and heated at 100° C. for 1hour. The cooled reaction mixture was concentrated in vacuo, dilutedwith ethyl acetate, washed with water, brine, dried over anhydrousmagnesium and concentrated. Chromatography of the residue on silica gel(elution gradient of acetonitrile in dichloromethane) gave 3.24 g (68%yield) of the title phosphonate as a clear oil. ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.44 (9H, s, t-Bu), 3.81 (3H, s, OCH₃), 3.84 (3H, s, OCH₃), 4.49(2H, d, J=6.0 Hz, NCH₂), 5.7 (1H, broad, NH), 7.24 (1H, m, aromatic),7.47–7.7 (2H, m, aromatics). HRMS (ESI⁺) calculated for C₁₄H₂₂FNO₅P[M+H⁺]: 334.1220. found: 334.1217.

Dimethyl 2-(aminomethyl)-5-fluorophenylphosphonate trifluoroacetic acidsalt. A solution of tert-butyl2-(dimethoxyphosphoryl)-4-fluorobenzylcarbamate (0.140 g, 0.42 mmol) indichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) andthe resulting mixture was stirred at 25° C. for 1 h. The solvent wasthen evaporated in vacuo to give the title amine salt as an amorphouswhite solid. MS (ESI⁺) m/z 234 [M+H⁺].

Benzyl hydrogen2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.A solution ofN-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.200 g, 0.35 mmol) in dimethyl sulfoxide (5 ml) was flushed with argonand then treated triethylamine (0.25 ml, 1.8 mmol),tetrakis(triphenylphosphine)palladium(0) (0.10 g) and dibenzyl phosphite(0.25 ml, 1.06 mmol). The reaction mixture was then sealed and heated at80° C. for 16 h. The reaction mixture was then diluted with ethylacetate, washed with 0.1 N hydrochloric acid, brine, dried overanhydrous magnesium sulfate and concentrated. Purification of theresidue by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm,elution gradient acetonitrile-water 0.1% trifluoroacetic acid) gave0.150 g (60% yield) of the title material as a white solid; mp 142° C.¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.58 (6H, s, 2×CH₃), 4.0 (4H, m, 2×CH₂),4.73 (2H, broad s, OCH₂), 5.05 (2H, d, J=8.6 Hz, NCH₂), 5.28 (2H, s,OCH₂), 7.20 (1H, m, aromatic), 7.29–7.34 (6H, m, aromatics), 7.45–7.64(6H, m, aromatics), 8.24 (1H, broad, NH). MS (ESI⁺) m/z 608 [M+H⁺].

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.White solid (77% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.01 (3H, t,J=7.4 Hz, CH₃), 1.9–2.0 (1H, m, CH), 2.2–2.35 (1H, m, CH), 2.47 (3H, s,CH₃), 3.8–3.9 (2H, m, CH₂), 4.1–4.35 (2H, m, CH₂), 4.4–4.5 (2H, m,NCH₂), 4.55 (1H, m, CH), 5.32 (2H, s, OCH₂), 7.07 (1H, dd, J=2.6 Hz andJ=8.6 Hz, aromatic), 7.17 (1H, m, aromatic), 7.24–7.28 (3H, m,aromatics), 7.4–7.45 (2H, m, aromatics), 7.71 (1H, dd, J=6.0 Hz andJ=8.6 Hz, aromatic), 8.31 (1H, s, CH), 8.48 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₇H₂₈FN₆O₄ [M+H⁺]: 519.2156. found: 519.2136.

N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.White solid (95% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.0 (3H, t,J=7.4 Hz, CH₃), 1.9–2.05 (1H, m, CH), 2.2–2.3 (1H, m, CH), 2.88 (6H, s,2×NCH₃), 3.8–3.9 (2H, m, CH₂), 4.1–4.35 (2H, m, CH₂), 4.52 (1H, m, CH),4.82 (2H, d, J=6.6 Hz, NCH₂), 5.36 (2H, s, OCH₂), 7.24 (1H, m,aromatic), 7.28–7.31 (3H, m, aromatics), 7.46–7.49 (2H, m, aromatics),7.54 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.74 (1H, dd, J=5.4 Hzand J=8.6 Hz, aromatic), 8.39 (1H, broad t, NH). HRMS (ESI⁺) calculatedfor C₂₆H₃₀FN₄O₆S [M+H⁺]: 545.1870. found: 545.1859.

N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.White crystals; mp 163° C. (ethyl acetate-hexane). (70% yield). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.03 (3H, t, J=7.4 Hz, CH₃), 1.9–2.05 (1H, m,CH), 2.25–2.35 (1H, m, CH), 2.46 (3H, s, CH₃), 3.75–3.9 (2H, m, CH₂),4.1–4.35 (4H, m, CH₂ and N CH₂), 4.53 (1H, m, CH), 5.35 (2H, ABq,J_(AB)=10.9 Hz), 7.0 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.20(1H, m, aromatic), 7.28–7.32 (3H, m, aromatics), 7.45–7.5 (2H, m,aromatics), 7.69 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 7.89 (1H, s,CH), 8.29 (1H, broad t, NH). Anal. Calcd for C₂₇H₂₇FN₆O₄: C, 62.54; H,5.24; N, 16.20. Found: C, 62.39; H, 5.36; N, 16.19.

N-(4-Fluoro-2-(1-methyl-1H-pyrazol-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution ofN-(4-fluoro-2-(1H-pyrazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.185 g, 0.36 mmol) in N,N-dimethylformamide (3 ml) was treated withiodomethane (0.025 ml, 0.4 mmol) and potassium carbonate (0.076 g, 0.55mmol) and the resulting mixture was stirred at 25° C. for 5 h. Thereaction mixture was then diluted with ethyl acetate, washed with water,brine, dried over anhydrous magnesium and concentrated. Chromatographyof the residue on silica gel (elution gradient of ethyl acetate indichloromethane) gave 0.120 g (64% yield) of the title compound as awhite solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.62 (6H, s, 2×CH₃), 3.84(3H, s, NCH₃), 3.95–4.05 (4H, m, 2×CH₂), 4.69 (2H, d, J=6.1 Hz, NCH₂),5.21 (2H, s, OCH₂), 6.49 (1H, d, J=2.2 Hz, CH), 7.01 (1H, m, aromatic),7.24–7.3 (4H, m, aromatics), 7.40 (1H, d, J=2.2 Hz, CH), 7.42–7.45 (2H,m, aromatics), 7.64 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.75 (1H,broad t, NH). HRMS (ESI⁺) calculated for C₂₈H₂₉FN₅O₄ [M+H⁺]: 518.2204.found: 518.2222.

N-(4-Fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.250 g, 0.44 mmol) was reacted with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.183 g, 0.88 mmol), sodium carbonate (0.150 g, 1.41 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.10 g) to give 0.152 g (65%yield) of the title material as a white solid after chromatography onsilica gel. ¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.63 (6H, s, 2×CH₃), 3.69(3H, s, NCH₃), 4.0–4.1 (4H, m, 2×CH₂), 4.34 (2H, d, J=6.6 Hz, NCH₂),5.29 (2H, s, OCH₂), 6.26 (1H, d, J=2.0 Hz, CH), 6.98 (1H, dd, J=2.5 Hzand J=8.6 Hz, aromatic), 7.13 (1H, m, aromatic), 7.3–7.35 (3H, m,aromatics), 7.47–7.55 (4H, m, aromatics and NH), 7.57 (1H, d, J=2.0 Hz,CH). MS (ESI⁺) m/z 518 [M+H⁺].

N-(2-(3-Methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.White crystals; mp 213–214° C. (ethyl acetate). (90% yield). ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.65 (6H, s, 2×CH₃), 2.50 (3H, s, CH₃), 3.99–4.15(4H, m, 2×CH₂), 4.50 (2H, d, J=6.5 Hz, NCH₂), 5.31 (2H, s, OCH₂),7.26–7.34 (4H, m, aromatics), 7.4–7.52 (4H, m, aromatics), 7.73–7.77(1H, m, aromatic), 8.27 (1H, s, CH), 8.46 (1H, broad t, NH). Anal. Calcdfor C₂₇H₂₈N₆O₄: C, 64.78; H, 5.63; N, 16.79. Found: C, 64.67; H, 5.41;N, 16.55.

Methyl hydrogen2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.A solution ofN-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.200 g, 0.35 mmol) in acetonitrile (5 ml) was flushed with argon andthen treated with N,N-diisopropylethylamine (0.25 ml, 1.4 mmol),triphenylphosphine (0.030 g), palladium(ll) acetate (0.040 g). anddimethyl phosphite (0.10 ml, 1.06 mmol). The reaction mixture was thenheated in a microwave oven at 120° C. for 40 min. The reaction mixturewas then diluted with ethyl acetate, washed with 0.1 N hydrochloricacid, brine, dried over anhydrous magnesium sulfate and concentrated.Purification of the residue by preparative HPLC (column YMC Pack C-18,5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroaceticacid) gave 0.120 g (64% yield) of the title material as a white solid.¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.62 (6H, s, 2×CH₃), 3.77 and 3.79 (3H, 2s, OCH₃), 3.95–4.05 (4H, m, 2×CH₂), 4.75 (2H, d, J=4.6 Hz, NCH₂), 5.32(2H, s, OCH₂), 7.22 (1H, m, aromatic), 7.3–7.35 (3H, m, aromatics),7.38–7.42 (2H, m, aromatics), 7.48–7.54 (1H, m, aromatic), 7.55–7.62(1H, m, aromatic), 8.54 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₅H₂₈FN₃O₇P [M+H⁺]: 532.1649. found: 532.1642.

A solution ofN-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.200 g, 0.35 mmol), 1,3,2-dioxaphosphorinan-2-one (0.115 g, 1.06 mmol)and N,N-diisopropylethylamine (0.25 ml, 1.4 mmol) in acetonitrile (5 ml)was flushed with argon and then treated with triphenylphosphine (0.025g) and palladium(II) acetate (0.040 g). The resulting mixture was thensealed and heated at 120° C. in a microwave oven for 20 min. The cooledreaction mixture was concentrated and chromatographed on silica gel(elution gradient of acetonitrile in dichloromethane) to give 0.073 g(38% yield) of intermediate 210 as an amorphous solid. ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.65 (6H, s, 2×CH₃), 3.97–4.05 (4H, m, 2×CH₂),4.34–4.42 (2H, m, CH₂), 4.62–4.67 (2H, m, CH₂), 4.80 (2H, d, J=6.5 Hz,NCH₂), 5.30 (2H, s, OCH₂), 7.22–7.4 (5H, m, aromatics), 7.52–7.57 (2H,m, aromatics), 7.71–7.78 (1H, m, aromatic), 8.77 (1H, broad t, NH). MS(ESI⁺) m/z 544 [M+H⁺].

In an alternative work-up, the above crude reaction mixture was dilutedwith ethyl acetate, washed with 0.1 N hydrochloric acid, brine, driedover anhydrous magnesium sulfate and concentrated. Purification of theresidue by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm,elution gradient acetonitrile-water 0.1% trifluoroacetic acid) gave0.092 g (45% yield) of 2-hydroxyethyl hydrogen2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate,intermediate 211 as a white solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.61(6H, s, 2×CH₃), 3.77 (2H, broad m, CH₂), 3.95–4.05 (4H, m, 2×CH₂), 4.10(2H, broad m, CH₂), 4.81 (2H, broad, NCH₂), 5.25 (2H, s, OCH₂), 7.1–7.19(1H, m, aromatic), 7.29–7.32 (3H, m, aromatics), 7.4–7.47 (3H, m,aromatics), 7.55–7.64 (1H, m, aromatic), 8.27 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₆H₃₀FN₃O₈P [M+H⁺]: 562.1755. found: 562.1774.

Bis(2-Hydroxyethyl)2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.A solution ofN-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.200 g, 0.35 mmol), 1,3,2-dioxaphosphorinan-2-one (0.115 g, 1.06 mmol)and N,N-diisopropylethylamine (0.25 ml, 1.4 mmol) in ethylene glycol (5ml) was flushed with argon and then treated with triphenylphosphine(0.025 g) and palladium(ll) acetate (0.040 g). The resulting mixture wasthen sealed and heated at 80° C. for 2 hour. The cooled reaction mixturewas diluted with ethyl acetate, washed with water, brine, dried overanhydrous magnesium and concentrated. The residue was purified bypreparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm, elution gradientacetonitrile-water 0.1% trifluoroacetic acid) to give 0.093 g (44%yield) of the title phosphonate as a clear oil. ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.63 (6H, s, 2×CH₃), 3.8–3.9 (4H, m, 2×CH₂), 4.0–4.1 (4H, m,2×CH₂), 4.15–4.3 (4H, m, 2×CH₂), 4.81 (2H, d, J=6.1 Hz, NCH₂), 5.29 (2H,s, OCH₂), 7.22–7.4 (6H, m, aromatics), 7.5–7.6 (2H, m, aromatics), 8.55(1H, broad t, NH). HRMS (ESI⁺) calculated for C₂₈H₃₄FN₃O₉P [M+H⁺]:606.2017. found: 606.2018.

Reaction ofN-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.350 g, 0.62 mmol) and 5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one(0.280 g, 1.86 mmol) with triphenylphosphine (0.035 g) and palladium(II)acetate (0.050 g) at 80° C. as described above gave 0.140 g (39% yield)of intermediate 213 as a white solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm):1.13 (3H, s, CH₃), 1.16 (3H, s, CH₃), 1.61 (6H, s, 2×CH₃), 3.9–4.05 (6H,m, 3×CH₂), 4.36 (2H, t, J=10.5 Hz, CH₂), 4.83 (2H, d, J=6.6 Hz, NCH₂),5.36 (2H, s, OCH₂), 7.25–7.33 (4H, m, aromatics), 7.4–7.5 (3H, m,aromatics), 7.7–7.75 (1H, m, aromatic), 8.76 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₉H₃₄FN₃O₇P [M+H⁺]: 586.2118. found: 586.2133.

2-Azido-1-bromo-4-fluorobenzene. 2-Bromo-5-fluoro aniline (2.00 g, 10.53mmol) was dissolved in concentrated HCl (10 mL) and water (10 mL) andcooled to 0° C. Aqueous NaNO₂ solution (1.090 g, 15.8 mmol of NaNO₂ in10 mL of water) was added dropwise at such a rate that the temperaturedid not exceed 5° C. This mixture was stirred at 0° C. for 1.5 h. Asolution of NaN₃ (1.027 g, 15.8 mmol) and NaOAc (12.95 g, 158 mmol) inwater (50 mL) was then added at 0–5° C. and the mixture was stirred foran additional 1 h at this temperature. The mixture was extracted withethyl acetate and the combined extracts were washed with brine and driedover Na₂SO₄. The filtrate was concentrated to afford the title compoundas a tan solid (2.188 g, 96%): ¹H NMR (400 MHz, CDCl₃): 7.53 (1H, dd,J=8.8, 5.6 Hz), 6.94 (1H, dd, J=8.8, 2.8 Hz), 6.79 (1H, ddd, J=8.8, 7.6,2.8 Hz).

1-(2-Bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole. Amixture of 2-azido-1-bromo-4-fluorobenzene (1.047 g, 4.85 mmol) andtrimethylsilylacetylene (2.01 mL, 14.54 mmol) in toluene (5 mL) washeated in a pressure vessel at 110° C. for 21.5 h. The reaction mixturewas concentrated in vacuo and the residue was purified with a Biotagesystem on silica gel with hexanes:ethyl acetate (9:1) gradient as theeluent to afford the title compound as a colorless oil (1.451 g, 95%yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.97 (1H, s), 7.74 (1H, dd,J=9.0, 5.4 Hz), 7.37 (1H, dd, J=8.5, 2.9 Hz), 7.16 (1H, ddd, J=8.8, 7.6,3.0 Hz), 0.40 (9H, s), LCMS (⁺ESI, M+H⁺) m/z 314/316.

1-(2-Bromo-5-fluorophenyl)-5-methyl-4-(trimethylsilyl)-1H-1,2,3-triazole.The title compound can be prepared according to the procedure providedfor 1-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.73–7.69 (1H, m), 7.20–7.16 (2H, m), 2.22(3H, s), 0.39 (9H, s); LCMS (⁺ESI, M+H⁺) m/z 328/330.

1-(2-Bromo-5-fluorophenyl)-4-tert-butyl-1H-1,2,3-triazole. The titlecompound can be prepared according to the procedure provided for1-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole ¹H NMR(400 MHz, CDCl₃) δ ppm: 7.68–7.75 (2H, m), 7.38 (1H, dd, J=8.5, 2.9 Hz),7.14 (1H, ddd, J=8.8, 7.6, 3.0 Hz), 1.43 (9H, s), LCMS (⁺ESI, M+H⁺) m/z298/300.

1-(2-Bromo-5-fluorophenyl)-4-((tert-butyldimethylsilyloxy)methyl)-1H-1,2,3-triazole.The title compound can be prepared according to the procedure providedfor 1-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.95 (1H, s), 7.75 (1H, dd, J=9.0, 5.4 Hz),7.38 (1H, dd, J=8.3, 3.0 Hz), 7.17 (1H, ddd, J=9.0, 7.5, 2.8 Hz), 4.96(2H, s), 0.93 (9H, s), 0.13 (6H, s), LCMS (⁺ESI, M+H⁺) m/z 386/388.

1-(2-Bromo-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)-1H-1,2,3-triazole.The title compound can be prepared according to the procedure providedfor 1-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.70–7.78 (2H, m), 7.19–7.30 (2H, m), 4.67(2H, s), 0.82 (9H, s), −0.03 (6H, s), LCMS (⁺ESI, M+H⁺) m/z 386/388.

1-(2-Bromo-5-fluorophenyl)-1H-1,2,3-triazole.1-(2-Bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (0.800g, 2.55 mmol) was dissolved in THF (10 mL) and tetrabutylammoniumfluoride (2.8 mL, 2.80 mmol, 1.0 M in THF) was added dropwise and thereaction mixture was stirred at 25° C. for 4 h. The resulting mixturewas concentrated in vacuo and the residue was purified with a Biotagesystem on silica gel with hexanes:ethyl acetate (8:2 to 7:3) gradient asthe eluent to afford the title compound as a white solid (0.36 g, 58%yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.06 (1H, d, J=1.0 Hz), 7.90 (1H,d, J=1.3 Hz), 7.76 (1H, dd, J=8.8, 5.3 Hz), 7.39 (1H, dd, J=8.3, 2.8Hz), 7.19 (1H, ddd, J=8.9, 7.5, 3.0 Hz), LCMS (⁺ESI, M+H⁺) m/z 242/244.

1-(2-Bromo-5-fluorophenyl)-5-methyl-1H-1,2,3-triazole. The titlecompound can be prepared according to the procedure provided for1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole ¹H NMR (400 MHz, CDCl₃) δppm: 7.76 (1H, dd, J=9.1, 5.3 Hz), 7.62 (1H, s), 7.19–7.26 (2H, m), 2.25(3H, s), LCMS (⁺ESI, M+H⁺) m/z 256/258.

(1-(2-Bromo-5-fluorophenyl)-1H-1,2,3-triazol-4-yl)methanol. The titlecompound can be prepared according to the procedure provided for1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole ¹H NMR (400 MHz, CDCl₃) δppm: 8.02 (1H, s), 7.75 (1H, dd, J=8.8, 5.3 Hz), 7.38 (1H, dd, J=8.2,2.9 Hz), 7.19 (1H, ddd, J=8.9, 7.5, 3.0 Hz), 4.94 (2H, s), LCMS (⁺ESI,M+H⁺) m/z 270/272.

4-Fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile. A mixture of1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole (0.603 g, 2.49 mmol), CuCN(0.245 g, 2.74 mmol), and 15 mL of NMP was subjected to microwaveirradiation at 150° C. for 0.5 h. The brown mixture was filtered overcelite and washed with DMF. This solution was treated with 10% aqueousNH₄OH (28–30% solution) and extracted with EtOAc. The combined organicphase were successively washed with 10% aqueous NH₄OH (28–30% solution),saturated aqueous NH₄Cl, water, brine and dried over Na₂SO₄. Theresulting mixture was concentrated in vacuo and the residue was purifiedwith a Biotage system on silica gel with hexanes:ethyl acetate (7:3 to6:4) gradient as the eluent to afford the title compound as a lightyellow solid (0.285 g, 61% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.40(1H, d, J=1.0 Hz), 7.96 (1H, s), 7.91 (1H, dd, J=8.6, 5.6 Hz), 7.77 (1H,dd, J=8.7, 2.4 Hz), 7.31–7.39 (1H, m).

4-Fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile. The titlecompound can be prepared according to the procedure provided for4-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile ¹H NMR (400 MHz, CDCl₃) δppm: 7.93 (1H, dd, J=8.7, 5.4 Hz), 7.67 (1H, s), 7.44 (1H, ddd, J=8.6,7.6, 2.5 Hz), 7.35 (1H, dd, J=8.1, 2.5 Hz), 2.39 (3H, s), LCMS (⁺ESI,M+H⁺) m/z 203.

2-(4-tert-Butyl-1H-1,2,3-triazol-1-yl)-4-fluorobenzonitrile. The titlecompound can be prepared according to the procedure provided for4-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile ¹H NMR (400 MHz, CDCl₃) δppm: 8.07 (1H, s), 7.87 (1H, dd, J=8.8, 5.6 Hz), 7.74 (1H, dd, J=8.8,2.5 Hz), 7.25–7.33 (1H, m), 1.45 (9H, s), LCMS (⁺ESI, M+H⁺) m/z 245.

4-Fluoro-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)benzonitrile. Thetitle compound can be prepared according to the procedure provided for4-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile ¹H NMR (400 MHz, CDCl₃) δppm: 8.34 (1H, s), 7.91 (1H, dd, J=8.7, 5.4 Hz), 7.74 (1H, dd, J=8.6,2.5 Hz), 7.35 (1H, ddd, J=8.8, 7.3, 2.5 Hz), 4.96 (2H, s), LCMS (⁺ESI,M+H⁺) m/z 219.

(4-Fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl)methanamine hydrochloride. ¹HNMR (400 MHz, DMSO-D6) δ ppm: 8.73 (1H, d, J=1.0 Hz), 8.53 (3H, brs),8.07 (1H, d, J=1.0 Hz), 7.91 (1H, dd, J=8.7, 5.9 Hz), 7.66 (1H, dd,J=9.2, 2.7 Hz), 7.60 (1H, td, J=8.5, 2.7 Hz), 3.92 (2H, q, J=5.6 Hz),LCMS (⁺ESI, M+H⁺) m/z 193.

(4-Fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanaminehydrochloride. ¹H NMR (400 MHz, DMSO-D6) δ ppm: 8.61 (2H, s), 7.98 (1H,dd, J=9.5, 6.2 Hz), 7.80 (1H, s), 7.61–7.67 (2H, m), 3.66 (2H, q, J=5.7Hz), 2.26 (3H, s), LCMS (⁺ESI, M+H⁺) m/z 206.

(2-(4-tert-Butyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl)methanaminehydrochloride. ¹H NMR (400 MHz, DMSO-D6) δ ppm: 8.55 (2H, brs), 8.52(1H, s), 7.89 (1H, dd, J=8.8, 6.1 Hz), 7.65 (1H, dd, J=9.3, 2.5 Hz),7.55 (1H, td, J=8.5, 2.5 Hz), 3.95 (2H, q, J=5.6 Hz), 1.36 (9H, s), LCMS(⁺ESI, M+H⁺) m/z 249.

(1-(2-(aminomethyl)-5-fluorophenyl)-1H-1,2,3-triazol-4-yl)methanolhydrochloride. ¹H NMR (400 MHz, DMSO-D6) δ ppm: 8.56 (1H, s), 8.50 (2H,s), 7.89 (1H, dd, J=8.7, 5.9 Hz), 7.63 (1H, dd, J=9.2, 2.7 Hz), 7.58(1H, td, J=8.5, 2.8 Hz), 4.65 (2H, s), 3.94 (2H, q, J=5.4 Hz), LCMS(⁺ESI, M+H⁺) m/z 223.

N-(2-Cyano-5-fluorophenyl)ethanesulfonamide. ¹H NMR 400 MHz (CDCl₃) δ(ppm): 7.65 (1H, dd, J=8.6, 5.8 Hz), 7.55 (1H, dd, J=10.2, 2.4 Hz), 6.96(1H, ddd, J=8.7, 7.5, 2.5 Hz), 3.27 (3H, q, J=7.3 Hz), 1.47 (4H, t,J=7.3 Hz)

N-(2-(aminomethyl)-5-fluorophenyl)ethanesulfonamide hydrochloride. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 7.56–7.64 (1H, m), 7.11–7.21 (2H, m) 4.25(2H, s), 3.15 (2H, q, J=7.3 Hz), 1.36 (3H, t, J=7.5 Hz)

(2-Bromo-5-fluoro-phenyl)-hydrazine hydrochloride. The title compoundwas synthesized according to the method described in U.S. Pat. No.3,959,309 (1976). To a stirred solution of 2-bromo-5-fluoroaniline (1)(100 g, 0.526 mol; Aldrich) in diethyl ether (600 mL) was addeddrop-wise concentrated hydrochloric acid (44 mL). After stirring foranother 20 min, the precipitate was filtered, washed thoroughly withdiethyl ether, and dried in vacuo to obtain 94.7 g of2-bromo-5-fluoroaniline hydrochloride as a white powder: HPLC rt=2.21min; ¹H NMR (DMSO-d6, 500 MHz) δ ppm 6.36 (1H, dt, J=8.5, 3 Hz, 5-CH),76.67 (1H, dd, J=11, 3 Hz, 3-CH), 7.36 (1H, dd, J=9, 6 Hz, 6-CH).

To a mechanically stirred suspension of 2-bromo-5-fluoroanilinehydrochloride (94.7 g, 0.418 mol; obtained above) in a mixture ofconc-HCl (250 mL) and water (250 mL) was added drop-wise a solution ofsodium nitrite, NaNO₂ (29 g, 0.420 mol) in water (60 mL) in adry-ice/acetone bath, maintaining the bath temperature at −5–0° C. overa period of 10–15 min. Additional NaNO₂ (1 g) was added and stirred atthe same temperature for 5 min to obtain a clear solution. To this clearsolution was added a solution of stannous chloride, SnCl₂ (276.8 g, 1.46mol) in conc-HCl (600 mL) drop-wise at 0–5° C. over a period of 30–40min. A precipitate starts forming immediately after the addition. Thisthick mixture was stirred for another 1.5 h, and the precipitate wascollected by suction-filtration, washed with a minimum amount of water(˜200 mL), then with diethyl ether, and dried in vacuo to obtain thetitle compound as an off-white powder: HPLC rt=0.73 min; LC/MS m/z 205(M+H); ¹H NMR (DMSO-d6, 500 MHz) δ ppm 6.78 (1H, dt, J=8.5, 3 Hz, 5-CH),7.04 (1H, dd, J=11, 3 Hz, 3-CH), 7.60 (1H, dd, J=8.5, 6 Hz, 6-CH), 8.15(1H, s, NH), 10.49 (3H, brs, NH₃ ⁺); ¹³C NMR (DMSO-d6, 125.8 Hz) δ ppm102.6 (d, J=28 Hz, 3-CH), 103.4 (d, J=2.6 Hz, 1-C), 109.0 (d, J=23 Hz,5-CH), 133.8 (d, J=9.6 Hz, 6-CH), 144.0 (d, J=10.7 Hz, 2-C), 161.7 (d,J=243 Hz, 4-CF).

1-(2-Bromo-5-fluoro-phenyl)-1H-pyrazole. A mixture of1-(2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (1.83 g, 7.58 mmol)and malonaldehyde bis(dimethylacetal) (1.27 g, 7.73 mmol) in EtOH (10mL) was heated at reflux under nitrogen for 1 h. After cooling themixture was diluted with diethyl ether (25 mL) and washed with water,and then with brine, dried (Na₂SO₄), filtered and concentrated to obtainthe title compound as a clear oil: HPLC rt=2.31 min. LC/MS m/z 241/243(M+H); ¹H NMR (CDCl₃, 500 MHz) δ ppm 6.47 (1H, m, 8-CH), 7.00–7.04 (1H,m, 5-CH), 7.31 (1H, dd, J=9, 3 Hz, 3-CH), 7.65 (1H, dd, J=8.8, 5.5 Hz,6-CH), 7.75 (1H, d, J=1.5 Hz, 9-CH), 7.89 (1H, d, J=2.5 Hz, 7-CH); ¹³CNMR (CDCl₃, 125.8 Hz) δ ppm 107.0 (8-CH), 112.2 (d, J=3.8 Hz, 1-C),115.8, (d, J=25 Hz, 3-CH), 116.8 (d, J=22 Hz, 5-CH), 131.3 (7-CH), 134.9(d, J=8.6 Hz, 6-CH), 140.9 (d, J=10 Hz, 2-C), 141.4 (9-CH), 161.9 (d,J=250 Hz, 4-CF); HRMS (ESI) calcd for C₉H₇FBrN₂ (M+H) 240.9777. found240.9769 (δ −3.1 ppm)

4-Fluoro-2-pyrazol-1-yl-benzonitrile. To a stirred suspension of CuCN(358 mg, 4.0 mmol, Aldrich) in DMF (2 mL, Sure Seal) was added asolution of 1-(2-Bromo-5-fluoro-phenyl)-1H-pyrazole (964 mg, 4.0 mmol)in DMF (2 mL) and the resulting clear solution was stirred in an oilbath heated at 110° C. under nitrogen for 1.5 h. After cooling, themixture was concentrated in vacuo and the residue mixed with 14% aqueousNH₄OH (10 mL) was stirred at room temperature for 0.5 h. To this wasadded EtOAc (15 mL) and the mixture stirred for additional 0.5 h. TheEtOAc extract was washed with dil. NH₄OH and then with brine, dried(Na₂SO₄), filtered, and concentrated. The residual oil was purified bycolumn chromatography (SiO₂, 0–10% EtOAc/CH₂Cl₂) to obtain 542 mg of thetitle compound as a white crystalline solid: TLC Rf 0.42 (CH₂Cl₂); HPLCrt=1.94 min. LC/MS m/z 188 (M+H); ¹H NMR (CDCl₃, 500 MHz) δ ppm 6.55(1H, dd, J=2.6, 1.7 Hz, 9-CH), 7.10–7.13 (1H, m, 5-CH), 7.59 (1H, dd,J=9.5, 2.5 Hz, 3-CH), 7.76 (1H, dd, J=8.7, 5.5 Hz, 6-CH), 7.80 (1H, d,J=1.2 Hz, 10-CH), 8.25 (1H, d, J=2.7 Hz, 8-CH); ¹³C NMR (CDCl₃, 125.8Hz) δ ppm 100.5 (d, J=3.8 Hz, 1-C), 109.1 (9-CH), 111.9 (d, J=27 Hz,3-CH), 114.9 (d, J=23 Hz, 5-CH), 116.6 (7-CN), 129.5 (8-CH), 136.7 (d,J=10 Hz, 6-CH), 142.8 (10-CH), 144.2 (d, J=12 Hz, 2-C), 165.5 (d, J=258Hz, 4-CF); HRMS (ESI) calcd for C₁₀H₇FN₃ (M+H) 189.0576. found 189.0568(δ −4.5 ppm); UV (MeOH) λ max 224 nm (ε 2.54×10⁴), 261 nm (ε 1.20×10⁴);Anal. calcd for C₁₀H₇FN₃: C, 64.16; H, 3.24; N, 22.45. found C, 64.02;H, 3.16; N, 22.68.

4-Fluoro-2-pyrazol-1-yl-benzylamine hydrochloride. To a solution of4-fluoro-2-pyrazol-1-yl-benzonitrile (500 mg, 2.67 mmol) in EtOH (10 mL)and EtOAc (10 mL) was added conc-HCl (0.25 mL, 3 mmol) and 10% Pd—C (100mg). The mixture was hydrogenated at 1 atmosphere hydrogen for 20 h. Tothe mixture was added additional conc-HCl (0.15 mL) and 10% Pd—C (100mg) and the mixture was further hydrogenated for additional 20 h. Themixture was filtered over Celite, washed with EtOH, and the combinedfiltrate and washings were concentrated in vacuo. The residual materialwas triturated with EtOH to obtain 356 mg of the title compound as thehydrochloride salt as an off-white crystalline solid: HPLC rt=1.01 min.LC/MS m/z 192 (M+H); ¹H NMR (DMSO-d6, 500 MHz) δ ppm 3.99 (2H, s,7-CH₂), 6.63 (1H, t, J=2 Hz, 9-CH), 7.40 (1H, dt, J=8.5, 2.5 Hz, 5-CH),7.54 (1H, dd, J=10, 2.5 Hz, 3-CH) 7.81 (1H, dd, J=8.5, 6 Hz, 6-CH), 7.86(1H, d, J=1.5 Hz, 10-CH) 8.35 (1H, d, J=2 Hz, 8-CH), 8.54 (3H, br.s, NH₃⁺); ¹³C NMR (DMSO-d6, 125.8 Hz) δ ppm 38.8 (7-CH₂), 107.7 (9-CH₂), 111.6(d, J=25 Hz, 3-CH), 114.6 (d, J=21 Hz, 5-CH), 123.7 (d, J=3 Hz, 1-C),131.7 (8-CH), 134.0 (d, J=9 Hz, 6-CH), 140.4 (d, J=11 Hz, 2-C), 141.5(10-CH), 161.9 (d, J=247 Hz, 6-CF); HRMS (ESI) calcd for C₁₀H₁₁FN₃ (M+H)192.0937. found 192.0930 (δ −3.6 ppm).

1-(2-Bromo-5-fluorophenyl)-3,5-dimethyl-1H-1,2,4-triazole. A mixture of1-(2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (24.15 g, 100 mmol)and diacetamide (10.1 g, 100 mmol; Aldrich) in anhydrous pyridine (100mL) was stirred in an oil bath heated at 125–130° C. under nitrogen for2 h. After cooling the mixture was concentrated in vacuo to dryness, andthe residue diluted with EtOAc (100 mL) was washed with water (50 mL),and then with brine (30 mL), dried (Na₂SO₄), filtered and concentratedto obtain 24.2 g of the title compound as a brownish oil: HPLC rt=1.59min. LC/MS m/z 270/272 (M+H); ¹H NMR (CDCl₃, 500 MHz) δ ppm 2.30 (3H, s,9-Me), 2.39 (3H, s, 10-Me), 7.10–7.15 (2H, m, 3,5-CH), 7.67 (1H, dd,J=8.5, 5.5 Hz, 6-H); ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm 12.4 (9-CH₃), 13.8(10-Me), 116.5 (d, J=4 Hz, 1-C), 117.2, (d, J=24 Hz, 3-CH), 118.9 (d,J=22 Hz, 5-CH), 134.7 (d, J=8.5 Hz, 6-CH), 137.8 (d, J=10 Hz, 2-C),153.9 (7-C), 160.9 (8-C), 161.8 (d, J=251 Hz, 4-CF); HRMS (ESI) calcdfor C₁₀H₁₀BrFN₃ (M+H) 270.0042. found 270.0048 (δ +2.2 ppm). Thistriazole was also prepared in 62% yield from1-(2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride and2,4,6-trimethyl-s-triazine by refluxing them in EtOH.

2-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorobenzonitrile LC/MS m/z217 (M+H). ¹H NMR (CDCl₃, 500 MHz) δ ppm 2.45 (3H, s, 11-Me), 2.49 (3H,s, 10-Me), 7.25 (1H, dd, J=8.5, 2.5 Hz, 3-CH), 7.31 (1H, dt, J=8.5, 2.5Hz, 5-CH), 7.87 (1H, dd, J=8.7, 5.6 Hz, 6-CH). ¹³C NMR (CDCl₃, 125.8 Hz)δ ppm 12.7 (10-Me), 13.8 (11-Me), 107.1 (d, J=3.8 Hz, 1-C), 114.8(7-CN), 116.2, (d, J=25 Hz, 3-CH), 117.6 (d, J=22 Hz, 5-CH), 136.0 (d,J=10 Hz, 6-CH), 141.6 (d, J=10 Hz, 2-C), 153.9 (8-C), 161.0 (9-C), 165.0(d, J=260 Hz, 4-CF). HRMS (ESI) calcd for C₁₁H₁₀FN₄ (M+H) 217.0889.found 271.0879 (δ −4.8 ppm). Anal. calcd for C₁₁H₉FN₄: C, 61.10; H,4.19; N, 25.91. found C, 60.78; H, 3.93; N, 26.05.

(2-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl)methanaminedihydrochloride. LC/MS m/z 221 (M+H). ¹H NMR (CD₃OD, 500 MHz) δ ppm 2.67(3H, s, 11-Me), 2.77 (3H, s, 10-Me), 4.16 (2H, s, 7-CH₂), 7.61 (1H, dt,J=8.5, 2.5 Hz, 5-CH), 7.67 (1H, dd, J=8.5, 2.4 Hz, 3-CH), 7.93 (1H, dd,J=8.8, 5.7 Hz, 6-CH). ¹³C NMR (CD₃OD, 125.8 MHz) δ ppm 10.5, 10.7(10,11-Me), 38.2 (7-CH₂), 115.1, (d, J=26 Hz, 3-CH), 119.3 (d, J=21 Hz,5-CH), 126.9 (d, J=3.8 Hz, 1-C), 134.5 (d, J=9.6 Hz, 6-CH), 135.3 (d,J=10.6 Hz, 2-C), 154.1, 154.4 (8,9-C), 163.1 (d, J=251 Hz, 4-CF). HRMS(ESI) calcd for C₁₁H₁₄FN₄ (M+H) 221.1202. found 221.1204 (δ −0.7 ppm);UV (MeOH) λ max 232 nm (ε 8.74×10³); Anal calcd forC₁₁H₁₃FN₄.2.2HCl.0.6H₂O: C, 42.47; H, 5.25; N, 18.01; C, 125.07; H₂O,3.48. found: 42.95; H, 4.80; N, 18.41; C, 124.56; H₂O, 3.00; (KF).

1-(2-bromo-5-fluorophenyl)-1H-1,2,4-triazole. Prepared according to theprocedure described in J. Org. Chem., 1956, 21, 1037. A stirred mixtureof (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (31.9 g, 0.132 mol)and s-triazine (10.7 g, 0.132 mol; Aldrich) in EtOH (250 mL) was heatedat 90° C. for 3 h. After cooling, the insoluble material was filteredoff and the filtrate was concentrated. The residue was partitionedbetween CH₂Cl₂ (200 mL) and water (200 mL), and the aqueous phase wasextracted once more with CH₂Cl₂ and the combined extracts were dried(MgSO₄), filtered and concentrated to a red semi-solid which wastriturated with hexanes to give 19.6 g of the title compound as anorange solid: HPLC rt=1.68 min. LC/MS m/z 242 (M+H); ¹H NMR (CDCl₃, 500MHz) δ ppm 7.02–7.15 (1H, m, 5-CH), 7.29 (1H, dd, J=8.4, 2.9 Hz, 3-CH),7.68 (1H, dd, J=8.8, 5.5 Hz, 6-CH), 8.10 (1H, s, 8-CH), 8.54 (1H, s,7-CH); ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm 112.54, 112.57 (d, J=1.5 Hz,1-C), 115.68, 115.88 (d, J=25 Hz, 3-CH), 118.07, 118.25 (d, J=22 Hz,5-CH), 135.11, 135.18 (d, J=8.6 Hz, 6-CH), 137.43, 137.52 (d, J=11 Hz,2-C), 144.4 (7-CH), 152.6 (8-CH), 160.95, 162.94 (d, J=251 Hz, 4-CF);HRMS (ESD) calcd for C₈H₆FBrN₃ (M+H) 241.9727. found 241.9733 (δ 1.6ppm); UV (MeOH) λmax 275 nm (ε 1.45×10³); Anal. calcd for C₈H₅BrFN₃: C,39.69; H, 2.08; N, 17.36. found C, 39.63; H, 1.83; N, 17.22.

(2-(2-Bromo-5-fluorophenyl)-2H-1,2,4-triazol-3-yl)methanol. A suspensionof 1-(2-bromo-5-fluorophenyl)-1H-1,2,4-triazole (3.63 g, 15 mmol) in 37%formaline (15 mL) in a sealed vessel was stirred in an oil bath heatedat 150° C. for 9.5 h. After cooling, the mixture was extracted withCH₂Cl₂ (15 mL×2) and the combined extracts were washed with brine, dried(Na₂SO₄), filtered and concentrated. The residual crude oil was purifiedby column chromatography (SiO₂, 0–7% MeOH/CH₂Cl₂) followed bytrituration with Et₂O to obtain 430 mg of the title compound as whitecrystalline solid: TLC Rf 0.5 (10% MeOH/CH₂Cl₂); HPLC rt=1.31 min; LC/MSm/z 272/274 (M+H); ¹H NMR (CDCl₃, 500 MHz) δ ppm 3.67 (1H, br.s, OH),4.65 (2H, s, 9-OCH₂), 7.13–7.22 (1H, m, 5-CH), 7.29 (1H, dd, J=8, 3 Hz,3-CH), 7.71 (1H, dd, J=9.0, 5.3 Hz, 6-CH), 8.03 (1H, s, 8-CH); ¹³C NMR(CDCl₃, 125.8 Hz) δ ppm 55.3 (9-OCH₂), 116.2 (d, J=3.9 Hz, 1-C), 117.4(d, J=25 Hz, 3-CH), 119.4 (d, J=22 Hz, 5-CH), 134.7 (d, J=8.3 Hz, 6-CH),137.0 (d, J=10 Hz, 2-C), 151.3 (8-CH), 156.3 (7-C), 161.8 (d, J=252 Hz,4-CF); HRMS (ESI) calcd for C₉H₈FBrN₃O (M+H) 271.9835. found 271.9828 (δ−2.5 ppm).

4-Fluoro-2-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-benzonitrile. Thiscompound was prepared from(2-(2-bromo-5-fluorophenyl)-2H-1,2,4-triazol-3-yl)methanol and CuCN inDMF at 125–130° C. for 5 h by the method used for the preparation of4-fluoro-2-pyrazol-1-yl-benzonitrile. Yield: 48% (beige solid) HPLCrt=1.11 min. LC/MS m/z 219 (M+H). ¹H NMR (CDCl₃, 500 MHz) δ ppm 2.39(1H, br.s, OH), 4.79 (2H, s, 9-OCH₂), 7.32–7.40 (1H, m, 5-CH), 7.50 (1H,d, J=8.2, 2.1 Hz, 3-CH), 7.87 (1H, dd, J=8.5, 5.5 Hz, 6-CH), 8.14 (1H,s, 9-CH). HRMS (ESI) calcd for C₁₀H₈FN₄O (M+H) 219.0682. found 219.0689(δ +3.1 ppm).

[2-(2-Aminomethyl-5-fluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-methanolhydrochloride. This compound was prepared from4-fluoro-2-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-benzonitrile by thehydrogenation method used for the preparation of4-fluoro-2-pyrazol-1-yl-benzylamine hydrochloride. Yield: 100% (grayishgreen powder). HPLC rt=0.33 min. LC/MS m/z 223 (M+H). ¹H NMR (DMSO-d6,500 MHz) δ ppm 3.76 (2H, q, J=5.8 Hz, 7-NCH₂), 4.55 (2H, s, 9-OCH₂),7.54–7.60 (1H, m, 5-CH), 7.62 (1H, dd, J=9, 2.6 Hz, 3-CH), 7.89 (1H, dd,J=8.7, 6.0 Hz, 6-CH), 8.26 (1H, s, 8-CH), 8.58 (3H, br.s, NH₃). ¹³C NMR(DMSO-d6, 125.8 Hz) δ ppm 37.1 (7-NCH₂), 54.2 (10-OCH₂), 114.6 (d, J=24Hz, 3-CH), 117.0 (d, J=21 Hz, 5-CH), 127.1 (d, J=3.8 Hz, 1-C), 132.2 (d,J=8.6 Hz, 6-CH), 136.9 (d, J=111 Hz, 2-C), 151.0 (9-CH), 156.3 (8-C),161.3 (d, J=247 Hz, 4-CF). HRMS (ESI) calcd for C₁₀H₁₂FN₄O (M+H)223.0995. found 223.0988 (δ −3.2 ppm).

EXAMPLE 1

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-. Amixture of intermediate 7, ethyl3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.036 g, 0.15 mmol) and 4-fluorobenzylamine (0.11 g, 0.87 mmol) inanhydrous ethyl alcohol (5 ml) and N,N-dimethylformamide (2 ml) washeated under reflux for 18 h. The solvent was then evaporated in vacuoand the residue was partitioned between ethyl acetate and 0.1 Nhydrochloric acid. The organic phase was washed with water, brine anddried over anhydrous sodium sulfate. Evaporation of the solvent andrecrystallization of the resulting solid from ethanol gave 0.023 g (47%yield) of the title amide as white crystals; mp 211° C. (ethylacetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 4.06 (4H, m, 2×CH₂), 4.59(2H, d, J=7.6 Hz, NCH₂), 4.61 (2H, s, OCH₂), 7.09 (2H, m, aromatics),7.33 (2H, m, aromatics), 7.84 (1H, broad t, NH), 12.06 (1H, s, OH). MS(ESI⁺) m/z 320 [M+H⁺].

EXAMPLE 2

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.Reaction of intermediate 7, ethyl3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.100 g, 0.42 mmol) with 4-fluoro-3-methylbenzylamine (0.23 g, 1.66mmol) as described in the preparation of example 1 gave 0.101 g (73%yield) of the title amide as white crystals; mp 206–208° C. (ethylacetate). ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.30 (3H, s, CH₃), 4.06 (4H, m,2×CH₂), 4.55 (2H, d, J=6.1 Hz, NCH₂), 4.60 (2H, s, OCH₂), 7.01 (1H, m,aromatic), 7.14 (2H, m, aromatics), 7.81 (1H, broad t, NH), 12.09 (1H,s, OH). MS (ESI⁺) m/z 334 [M+H⁺].

EXAMPLE 3

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from intermediate 150,N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.79 (3H, d, J=4.5 Hz, NCH₃), 3.83 (2H,m, CH₂), 4.02 (2H, m, CH₂), 4.54 (2H, d, J=6.7 Hz, NCH₂), 4.58 (2H, s,OCH₂), 7.31 (2H, m, aromatics), 7.38 (1H, m, aromatic), 8.54 (1H, broadq, NH), 9.21 (1H, broad t, NH), 12.24 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₇H₁₈FN₄O₅ [M+H⁺]: 377.1261. found: 377.1249.

EXAMPLE 4

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(0.050 g, 0.20 mmol) with 4-fluorobenzylamine (0.11 g, 0.87 mmol) asdescribed in the preparation of example 1 gave 0.056 g (84% yield) ofthe title amide as white crystals; mp 165–167° C. (ethylacetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.62 (3H, d, J=7.0 Hz,CH₃), 3.90 (2H, m, CH₂), 4.15–4.32 (2H, m, CH₂), 4.61 (3H, m, NCH₂ andOCH), 7.08 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.82 (1H, broadt, NH), 12.06 (1H, s, OH). Anal. Calcd for C₁₆H₁₆FN₃O₄: C, 57.65; H,4.83; N, 12.60. Found: C, 57.44; H, 4.69; N, 12.37.

EXAMPLE 5

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.090 g, 0.35 mmol) with 4-fluoro-3-methylbenzylamine (0.180 g, 1.3mmol) as described in the preparation of example 1 gave 0.068 g (55%yield) of the title amide as white crystals; mp 134° C. (ethylacetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.62 (3H, d, J=6.6 Hz,CH₃), 2.30 (3H, s, CH₃), 3.90 (2H, m, CH₂), 4.13–4.32 (2H, m, CH₂),4.49–4.64 (3H, m, NCH₂ and OCH), 7.01 (1H, m, aromatic), 7.16 (2H, m,aromatics), 7.79 (1H, broad t, NH), 12.09 (1H, s, OH). Anal. Calcd forC₁₇H₁₈FN₃O₄: C, 58.78; H, 5.22; N, 12.09. Found: C, 58.57; H, 5.55; N,11.90.

EXAMPLE 6

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dichlorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(0.075 g, 0.29 mmol) with 3,4-dichlorobenzylamine (0.140 g, 0.8 mmol) asdescribed in the preparation of example 1 gave 0.085 g (75% yield) ofthe title amide as white crystals; mp 192° C. (ethyl acetate-hexane).¹HNMR 400 MHz (CDCl₃) δ ppm: 1.64 (3H, d, J=6.6 Hz, CH₃), 3.91 (2H, m,CH₂), 4.17–4.32 (2H, m, CH₂), 4.50–4.68 (3H, m, NCH₂ and OCH), 7.20 (1H,dd, J=2.0 Hz and J=8.0 Hz, aromatic), 7.44 (1H, d, J=2.0 Hz, aromatic),7.46 (1H, d, J=8.0 Hz, aromatic), 7.86 (1H, broad t, NH), 11.92 (1H, s,OH). MS (ESI⁺) m/z 384 [M+H⁺]. Anal. Calcd for C₁₆H₁₅Cl₂N₃O₄: C, 50.02;H, 3.94; N, 10.94. Found: C, 49.40; H, 4.06; N, 10.41.

EXAMPLE 7

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-chloro-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.075 g, 0.30 mmol) with 3-chloro-4-fluorobenzylamine (0.14 g, 0.88mmol) as described in the preparation of example 1 gave 0.050 g (46%yield) of the title amide as white crystals; mp 172° C. (ethylacetate-ether). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (3H, d, J=6.6 Hz,CH₃), 3.91 (2H, m, CH₂), 4.17–4.32 (2H, m, CH₂), 4.50–4.67 (3H, m, NCH₂and OCH), 7.16 (1H, m, aromatic), 7.24 (1H, m, aromatic), 7.40 (1H, m,aromatic), 7.85 (1H, broad t, NH), 11.95 (1H, s, OH). Anal. Calcd forC₁₆H₁₅ClFN₃O₄: C, 52.25; H, 4.11; N, 11.42. Found: C, 51.99; H, 4.01; N,11.09.

EXAMPLE 8

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.075 g, 0.30 mmol) with 3,4-dimethylbenzylamine (0.15 g, 1.1 mmol) asdescribed in the preparation of example 1 gave 0.033 g (33% yield) ofthe title amide as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.61 (3H,d, J=6.6 Hz, CH₃), 2.28 (3H, s, CH₃), 2.29 (3H, s, CH₃), 3.90 (2H, m,CH₂), 4.16–4.30 (2H, m, CH₂), 4.50–4.65 (3H, m, NCH₂ and OCH), 7.08–7.17(3H, m, aromatics), 7.78 (1H, broad t, NH), 12.17 (1H, s, OH). MS (ESI⁺)m/z 344 [M+H⁺].

EXAMPLE 9

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.A solution of intermediate 140,N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.268 g, 0.56 mmol) in a mixture of ethyl acetate (25 ml) and ethanol(25 ml) was hydrogenated under 1 atm of hydrogen at 25° C. over 10%palladium on activated carbon (0.09 g) for 2.5 h to give 0.121 g (56%yield) of the title ester as a white solid. ¹HNMR 400 MHz (DMSO-d₆) δppm: 1.57 (3H, d, J=6.7 Hz, CH₃), 2.79 (3H, d, J=4.6 Hz, NCH₃), 3.70(1H, m, CH), 3.87 (1H, m, CH), 3.98 (1H, m, CH), 4.15 (1H, m, CH), 4.55(2H, m, NCH₂), 4.62 (1H, q, J=6.6 Hz, OCH), 7.25–7.44 (3H, m,aromatics), 8.59 (1H, broad q, NH), 9.39 (1H, broad, NH), 12.18 (1H, s,OH). HRMS (ESI⁺) calculated for C₁₈H₂₀FN₄O₅ [M+H⁺]: 391.1418. found:391.1431.

EXAMPLES 10–14

Examples 10–14 can be prepared from ethyl9-ethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the method described for thesynthesis of example 1. Ethyl9-ethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylatewas prepared according to the method used to prepare intermediate 15.

EXAMPLE 10

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from 4-fluorobenzylamine. ¹HNMR 400MHz (CDCl₃) δ ppm: 1.02 (3H, t, J=7.3 Hz, CH₃), 1.93 (1H, m, CH), 2.15(1H, m, CH), 3.88 (2H, m, CH₂), 4.2–4.29 (2H, m, CH₂), 4.46 (1H, m, CH),4.53–4.69 (2H, m, CH₂), 7.06 (2H, m, aromatics), 7.34 (2H, m,aromatics), 7.82 (1H, broad t, NH), 12.05 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₇H₁₉FN₃O₄ [M+H⁺]: 348.1360. found: 348.1355.

EXAMPLE 11

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from(4-fluoro-3-methylphenyl)methanamine. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.01(3H, t, J=7.4 Hz, CH₃), 1.91 (1H, m, CH), 2.16 (1H, m, CH), 2.30 (3H, s,CH₃), 3.87 (2H, m, CH₂), 4.2–4.30 (2H, m, CH₂), 4.46 (1H, m, CH),4.48–4.65 (2H, m, CH₂), 7.01 (1H, m, aromatic), 7.14 (2H, m, aromatics),7.81 (1H, broad t, NH), 12.07 (1H, s, OH). Anal. Calcd for C₁₈H₂₀FN₃O₄:C, 59.82; H, 5.57; N, 11.62. Found: C, 59.53; H, 5.86; N, 11.42.

EXAMPLE 12

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dichlorophenyl)methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from (3,4-dichlorophenyl)methanamine.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.00 (3H, t, J=7.3 Hz, CH₃), 1.91 (1H, m,CH), 2.15 (1H, m, CH), 3.85 (2H, m, CH₂), 4.19–4.28 (2H, m, CH₂), 4.45(1H, m, CH), 4.48–4.66 (2H, m, CH₂), 7.19 (1H, m, aromatic), 7.43 (2H,m, aromatics), 7.84 (1H, broad t, NH), 11.88 (1H, s, OH). Anal. Calcdfor C₁₇H₁₇Cl₂N₃O₄: C, 51.27; H, 4.30; N, 10.55. Found: C, 51.16; H,4.21; N, 10.34.

EXAMPLE 13

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dimethylphenyl)methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from (3,4-dimethylphenyl)methanamine.¹HNMR 400 MHz (CDCl₃) δ ppm: 0.98 (3H, t, J=7.3 Hz, CH₃), 1.87 (1H, m,CH), 2.12 (1H, m, CH), 2.26 (3H, s, CH₃), 2.27 (3H, s, CH₃), 3.83 (2H,m, CH₂), 4.17–4.26 (2H, m, CH₂), 4.41 (1H, m, CH), 4.45–4.64 (2H, m,CH₂), 7.05–7.24 (3H, m, aromatics), 7.75 (1H, broad t, NH), 12.13 (1H,s, OH). Anal. Calcd for C₁₉H₂₃N₃O₄: C, 63.85; H, 6.49; N, 11.76. Found:C, 63.55; H, 6.48; N, 11.74.

EXAMPLE 14

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-chloro-4-fluorophenyl)methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from(3-chloro-4-fluorophenyl)methanamine. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.03(3H, t, J=7.3 Hz, CH₃), 1.92 (1H, m, CH), 2.17 (1H, m, CH), 3.88 (2H, m,CH₂), 4.18–4.32 (2H, m, CH₂), 4.46 (1H, m, CH), 4.5–4.68 (2H, m, CH₂),7.16 (1H, m, aromatic), 7.24 (1H, m, aromatic), 7.40 (1H, m, aromatic),7.84 (1H, broad t, NH), 11.93 (1H, s, OH). Anal. Calcd forC₁₇H₁₇ClFN₃O₄: C, 53.48; H, 4.48; N, 11.00. Found: C, 53.25; H, 4.49; N,10.79.

EXAMPLES 15–16

Examples 15–16 can be prepared from3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid and the indicated amines according to the methods described for thesynthesis of intermediate 140 and example 9.3-(Benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid was prepared according to the method used to prepare intermediate16.

EXAMPLE 15

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from intermediate 39. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.03 (3H, t, J=7.3 Hz, CH₃), 1.98 (1H, m, CH), 2.28 (1H,m, CH), 3.06 (3H, d, J=4.5 Hz, NCH₃), 3.86 (2H, m, CH₂), 4.14–4.29 (2H,m, CH₂), 4.48 (1H, m, CH), 4.60 (2H, m, CH₂), 6.2 (1H, broad, NH),7.14–7.21 (2H, m, aromatics), 7.54 (1H, m, aromatic), 8.85 (1H, broad t,NH), 12.1 (1H, s, OH). HRMS (ESI⁺) calculated for C₁₉H₂₂FN₄O₅ [M+H⁺]:405.1574. found: 405.1579.

EXAMPLE 16

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from intermediate 151,N-(4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,according to a procedure similar to that described in example 9. ¹HNMR400 MHz (DMSO-d₆) δ ppm: 0.94 (3H, t, J=7.5 Hz, CH₃), 1.88 (1H, m, CH),2.27 (1H, m, CH), 3.68 (1H, m, CH), 3.87 (1H, m, CH), 4.0 (1H, m, CH),4.19 (1H, m, CH), 4.36–4.49 (3H, m, CH₂ and CH), 7.43 (1H, m, aromatic),7.56 (2H, m, aromatics), 8.32 (1H, m, CH), 9.05 (1H, m, CH), 9.3 (1H,broad t, NH), 12.04 (1H, s, OH). HRMS (ESI⁺) calculated for C₁₉H₂₀FN₆O₄[M+H⁺]: 415.1530. found: 415.1515.

EXAMPLES 17–18

Examples 17–18 can be prepared from ethyl3-hydroxy-9-isopropyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the method described for thesynthesis of example 1. Ethyl3-hydroxy-9-isopropyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylatecan be prepared according to the method used to prepare intermediate 15.

EXAMPLE 17

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-(1-methylethyl)-4-oxo-.The title compound can be prepared from 4-fluorobenzylamine. ¹HNMR 400MHz (CDCl₃) δ ppm: 0.80 (3H, d, J=6.7 Hz, CH₃), 1.13 (3H, d, J=7.1 Hz,CH₃), 2.54 (1H, m, CH), 3.77 (2H, m, CH₂), 4.3 (2H, m, CH₂), 4.40 (1H,d, J=2.5 Hz, CH), 4.50–4.72 (2H, m, CH₂), 7.09 (2H, m, aromatics), 7.34(2H, m, aromatics), 7.82 (1H, broad t, NH), 12.04 (1H, s, OH). Anal.Calcd for C₁₈H₂₀FN₃O₄: C, 59.82; H, 5.57; N, 11.62. Found: C, 59.22; H,5.81; N, 11.50.

EXAMPLE 18

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-(1-methylethyl)-4-oxo-.The title compound can be prepared from(4-fluoro-3-methylphenyl)methanamine. ¹HNMR 400 MHz (CDCl₃) δ ppm: 0.80(3H, d, J=6.6 Hz, CH₃), 1.13 (3H, d, J=7.1 Hz, CH₃), 2.30 (3H, s, CH₃),2.54 (1H, m, CH), 3.77 (2H, m, CH₂), 4.3 (2H, m, CH₂), 4.40 (1H, broads, CH), 4.46–4.68 (2H, m, CH₂), 7.02 (1H, m, aromatic), 7.17 (2H, m,aromatics), 7.80 (1H, broad t, NH), 12.07 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₉H₂₃FN₃O₄ [M+H⁺]: 376.1673. found: 376.1671.

EXAMPLE 19

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To a solution of intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(3.0 g, 11.19 mmol) in DMF (20 mL) and ethanol (10 mL) was addedtriethylamine (1.55 mL) followed by 4-fluorobenzylamine (3.82 mL, 33.57mmol). The mixture was stirred at 90° C. for 2 h and then concentrated.The resultant oil was partitioned between ethyl acetate (50 mL) and 1Naqueous HCl (35 mL). The aqueous layer was back-extracted with ethylacetate (20 mL) and the organic layers were combined and washed with H₂O(4×20 mL) and brine then dried (Na₂SO₄) and concentrated. The brownresidue was triturated with ether and the solids filtered and washedwith ether. The pale brown solids were recrystallized from 95:5 MeOH/H₂Oto give the title compound as colorless needles (3.18 g, 82% yield). ¹HNMR (500 MHz, CDCl₃) δ ppm: 11.96 (1H, s), 7.77 (1H, brs), 7.30 (2H, dd,J=8.4, 5.3 Hz), 7.04 (2H, t, J=8.7 Hz), 4.57 (2H, d, J=6.1 Hz), 4.01(4H, s), 1.56 (6H, s). HRMS (M+H) calcd for C₁₇H₁₉FN₃O₄: 348.13597.found: 348.1365. Anal calcd for C₁₇H₁₈FN₃O₄: C, 58.78; H, 5.22; N,12.09. Found: C, 58.38; H, 5.23; N, 11.80.

Additional procedure. Ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(50 g, 0.186 mol) and ethanol SDA3A (500 mL) was added to a 1 L roundbottom flask equipped with a mechanical stirrer, nitrogen inlet-outlet,temperature probe, and condenser. Triethylamine (18.86 g, 0.186 mol) wasadded to the slurry. The resulting solution was heated to 35° C.followed by slow addition of 4-fluorobenzylamine (35.0 g, 0.279 mol).The thick slurry was heated at 78° C. with stirring for 6 h. Thereaction mixture was polish filtered and the filtrate reheated to 70° C.The pH was adjusted to about 1.0 by slow addition of 1N HCl (405 mL).The thick slurry was cooled to 20–25° C., the solids filtered off,washed twice with ethanol SDA 3A (each 250 mL) and twice with water(each 500 mL). The white solid was dried in vacuo at 50–55° C. to affordN-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide(58.9 g).

Additional procedure. To a stirring mixture of ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(5.18 g, 19.31 mmol) and EtOH SDA3A (52 mL) was added triethylamine(1.95 g, 19.30 mmoles) under inert atmosphere. The resulting solutionwas heated to 40° C. and 4-fluorobenzylamine (3.58 g, 28.61 mmol) wasadded slowly over about 3 min. The resulting white slurry was heated to78–79° C. giving a solution which was held with stirring for 6 h. Thehot solution was polish filtered. The pH of the filtrate was adjusted toabout 2.5 by slow addition of 1M H₂SO₄ (18.1 mL) at 65–70° C. Theresulting thick slurry was allowed to cool slowly to 20–25° C. The solidwas collected by filtration, washed with EtOH SDA 3A (2×25 mL) and water(2×25 mL). The solid was dried in vacuo at 50° C. to affordN-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamideas a white crystalline solid (6.02 g).

EXAMPLE 20

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A DMF solution of intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(4 mL, 1 mmol), Et₃N (0.14 mL, 1 mmol) and 3-methy-4-fluorobenzylamine(0.418 g, 3 mmol) was heated at 90° C. for 5 h. The reaction mixture wascooled and the product isolated by reverse phase preparative HPLC usingMeOH/H₂O-0.1% CF₃CO₂H as eluent. The fractions containing the desiredmaterial were combined and concentrated to afford the title compound asa yellow powder (0.19 g, 52% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm:11.99 (1H, s), 7.73 (1H, s), 7.14 (1H, d, J=7.3 Hz), 7.12–7.09 (1H, m),6.98 (1H, t, J=9.0 Hz), 4.54 (2H, d, J=6.4 Hz), 4.01 (4H, s), 2.27 (3H,s), 1.56 (6H, s). HRMS (M+H) calcd for C₁₈H₂₁FN₃O₄: 362.1516. found:362.1509. Anal calcd for C₁₈H₂₀FN₃O₄+0.07H₂O: C, 59.26; H, 5.55; N,11.48. Found: C, 58.88; H, 5.36; N, 11.34.

EXAMPLES 21–41

Examples 21–41 can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,and the indicated amines according to the method described for thesynthesis of examples 1, 19 and 20.

EXAMPLE 21

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 69. Solid, ¹H NMR(500 MHz, DMSO-d₆) δ ppm: 11.93 (1H, s), 9.29 (1H, t, J=6.2 Hz), 9.05(1H, s), 8.32 (1H, s), 7.57–7.53 (2H, m), 7.43 (1H, td, J=7.9, 1.7 Hz),4.44 (2H, d, J=6.1 Hz), 3.98 (2H, t, J=4.9 Hz), 3.83 (2H, t, J=4.9 Hz),1.56 (6H, s). HRMS (M+H) calcd for C₁₉H₂₀N₆O₄F: 415.15302. found:415.1520. Anal Calcd for C₁₉H₁₉N₆O₄F: C, 55.07; H, 4.62; N, 20.28; F,4.58. found: C, 54.95; H, 4.67; N, 20.27; F, 4.56.

EXAMPLE 22

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 70. Solid, ¹H NMR(500 MHz, DMSO-d₆) δ ppm: 12.07 (1H, s), 9.46 (1H, bs), 9.33 (1H, s),8.26 (1H, s), 7.81 (1H, dd, J=11.1, 2.0 Hz), 7.73 (1H, dd, J=8.2, 1.8Hz), 7.52 (1H, t, J=8.2 Hz), 4.59 (2H, d, J=6.1 Hz), 3.98 (2H, t, J=5.0Hz), 3.84 (2H, t, J=5.0 Hz), 1.58 (6H, s). HRMS (M+H) calcd forC₁₉H₂₀N₆O₄F: 415.15302. found: 415.1520. Anal calcd forC₁₉H₁₉N₆O₄F+1.25H₂O: C, 52.23; H, 4.96; N, 19.23; F, 4.35. found: C,52.29; H, 4.66; N, 19.23; F, 4.35.

EXAMPLE 23

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(4-morpholinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 73. Solid, ¹H NMR(500 MHz, CDCl₃) δ ppm: 12.09 (1H, s), 7.91 (1H, brs), 7.31–7.28 (1H,m), 6.90 (1H, dd, J=10.4, 2.4 Hz), 6.84 (1H, td, J=8.1, 2.4 Hz), 4.66(2H, d, J=6.4 Hz), 4.02 (4H, s), 3.89–3.87 (4H, m), 2.94–2.92 (4H, m),1.59 (6H, s). HRMS (M−H) calcd for C₂₁H₂₄N₄O₅F: 431.17307. found:431.1719. Anal calcd for C₂₁H₂₅N₄O₅F: C, 58.32; H, 5.82; N, 12.95; F,4.39. found: C, 58.13; H, 5.81; N, 12.79; F, 4.33.

EXAMPLE 24

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-fluoro-4-(4-morpholinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 74. ¹H NMR (500MHz, CDCl₃) δ ppm: 12.01 (1H, s), 7.80 (1H, brs), 7.28–7.24 (1H, m),6.66 (1H, d, J=8.5 Hz), 6.61 (1H, dd, J=13.4, 1.8 Hz), 4.56 (2H, d,J=6.1 Hz), 4.01 (4H, s), 3.85–3.84 (4H, m), 3.17–3.15 (4H, m), 1.60 (6H,s). HRMS (M−H) calcd for C₂₁H₂₄N₄O₅F: 431.17307. found: 431.1729. Analcalcd for C₂₁H₂₅N₄O₅F: C, 58.32; H, 5.82; N, 12.95; F, 4.39. found: C,58.23; H, 5.73; N, 12.82; F, 4.21.

EXAMPLE 25

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[3-(3,4-dichlorophenyl)propyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from3-(3,4-dichlorophenyl)propan-1-amine. ¹H NMR (500 MHz, CDCl₃) δ ppm:12.05 (1H, s), 7.46 (1H, brs), 7.35 (1H, d, J=8.2 Hz), 7.28 (1H, d,J=2.1 Hz), 7.04 (1H, dd, J=8.2, 2.1 Hz), 4.02 (4H, s), 3.46 (2H, q,J=6.9 Hz), 2.67 (2H, t, J=7.6 Hz), 1.95 (2H, m), 1.59 (6H, s). HRMS(M+H) calcd for C₁₉H₂₂N₃O₄Cl₂: 426.09875. found: 426.0996. Anal calcdfor C₁₉H₂₁N₃O₄Cl₂: C, 53.53; H, 4.96; N, 9.85; Cl, 16.63. found: C,53.57; H, 4.96; N, 9.76; Cl, 16.63.

EXAMPLE 26

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[3-(4-fluorophenyl)propyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from3-(4-fluorophenyl)propan-1-amine. ¹H NMR (500 MHz, CDCl₃) δ ppm: 12.09(1H, s), 7.15 (2H, dd, J=8.2, 5.5 Hz), 6.97 (2H, t, J=8.5 Hz), 4.02 (4H,s), 3.44 (2H, q, J=13.9, 6.9 Hz), 2.68 (2H, t, J=7.6 Hz), 1.98–1.92 (2H,m), 1.62 (6H, s). HRMS (M+H) calcd for C₁₉H₂₃N₃O₄F: 376.16727. found:376.1687. Anal calcd for C₁₉H₂₂N₃O₄F: C, 60.79; H, 5.90; N, 11.19; F,5.06. found: C, 60.70; H, 5.87; N, 11.14; F, 4.92.

EXAMPLE 27

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 76. ¹H NMR (500MHz, CDCl₃) δ ppm: 12.07 (1H, s), 8.31 (1H, d, J=6.44 Hz), 7.46 (1H, dd,J=8.5, 6.4 Hz), 7.19 (1H, dd, J=9.0, 2.6 Hz), 7.08 (1H, td, J=8.2, 2.7Hz), 4.92 (1H, dd, J=14.0, 8.8 Hz), 4.37 (1H, dd, J=14.0, 3.4 Hz),4.02–3.97 (2H, m), 3.99 (2H, s), 3.87–3.82 (1H, m), 3.45–3.41 (1H, m),3.30–3.20 (2H, m), 2.46–2.32 (2H, m), 2.00–1.88 (2H, m), 1.57 (3H, s),1.53 (3H, s). HRMS (M−H) calcd for C₂₁H₂₆N₄O₆FS: 481.15572. found:481.1570. Anal calcd for C₂₁H₂₅N₄O₆FS: C, 52.49; H, 5.24; N, 11.66; F,3.95; S, 6.67. found: C, 52.29; H, 5.37; N, 11.40; F, 3.91; S, 6.70.

EXAMPLE 28

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,5-difluoro-2-pyridinyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 102. ¹H NMR (500MHz, CDCl₃) δ ppm: 11.86 (1H, s), 8.58 (1H, brs), 8.33 (1H, d, J=2.4Hz), 7.27–7.24 (1H, m), 4.76 (2H, d, J=5.2 Hz), 4.03 (4H, s), 1.63 (6H,s). HRMS (M+H) calcd for C₁₆H₁₇F₂N₄O₄: 367.1218. found: 367.1230.

EXAMPLE 29

N-((5-Chloropyridin-2-yl)methyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 103. ¹H NMR (500MHz, CDCl₃) δ ppm: 11.80 (1H, brs), 8.64 (1H, brs), 8.57 (1H, d, J=2.4Hz), 7.78 (1H, dd, J=8.6, 2.4 Hz), 7.44 (1H, d, J=8.6 Hz), 4.72 (2H, d,J=6.1 Hz), 4.02 (4H, s), 1.61 (6H, s). HRMS (M+H) calcd forC₁₇H₁₈ClN₄O₄: 365.1017. found: 365.1028. Anal calcd forC₁₆H₁₇ClN₄O₄.0.25H₂O.0.5 CF₃CO₂H: C, 47.90; H, 4.26; N, 13.14; Cl, 8.32.found: C, 47.88; H, 3.98; N, 12.94; Cl, 8.57.

EXAMPLE 30

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-bromo-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(3-bromo-4-fluorophenyl)methanamine. Off white solid, ¹H-NMR (500 MHz,CDCl₃) δ ppm: 11.88 (1H, s), 7.76–7.84 (1H, br), 7.53 (1H, dd, J=6.3,2.0 Hz), 7.26–7.29 (H, m), 7.07–7.14 (1H, m), 4.57 (2H, d, J=6.4 Hz),4.02 (4H, s), 1.58 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 168.41,157.79, 151.99, 146.52, 134.91, 132.89, 128.44, 128.39, 125.30, 117.04,116.86, 77.69, 75.84, 58.21, 43.22, 41.98, 28.11. HRMS [M+H]⁺ calcd forC₁₇H₁₈N₃O₄FBr: 426.04648. found: 426.0468.

EXAMPLE 31

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (3,4-dimethylphenyl)methanamine.Off white solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.74 (1H), 7.04–7.15(3H, m), 4.56 (2H, d, J=5.8 Hz), 4.00–4.07 (4H, m), 2.27 (3H, s), 2.26(3H, s), 1.57 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 167.92, 158.58,151.61, 146.22, 137.37, 136.47, 134.53, 130.23, 129.11, 126.12, 125.12,75.93, 58.10, 43.42, 43.00, 28.04, 19.85, 19.53. HRMS [M+H]⁺ calcd forC₁₉H₂₄N₃O₄: 358.17669. found: 358.1783.

EXAMPLE 32

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-chloro-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(3-chloro-4-fluorophenyl)methanamine. Off white solid, ¹H-NMR (500 MHz,CDCl₃) δ ppm: 11.88 (1H, br s), 7.80 (1H, t, J=5.5 Hz), 7.38 (1H, dd,J=6.7, 2.1 Hz), 7.19–7.23 (1H, m), 7.13 (1H, t, J=8.5 Hz), 4.57 (2H, d,J=6.4 Hz), 4.02 (4H, s), 1.58 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm:168.41, 157.82, 151.99, 146.52, 134.54, 130.02, 127.58, 127.52, 125.32,121.61, 117.18, 117.01, 75.84, 58.21, 43.23, 42.08, 28.11. HRMS [M+H]⁺calcd for C₁₇H₁₈N₃O₄FCl: 382.09644. found: 382.0980.

EXAMPLE 33

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-difluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (3,4-difluorophenyl)methanamine.Light brown solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.77 (1H), 7.30–7.36(2H, m), 7.27 (1H, s), 4.59 (2H, d, J=6.4 Hz), 4.01–4.06 (4H, m), 1.58(6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 168.22, 158.36, 151.98, 151.17,146.35, 134.33, 125.74, 123.70, 123.67, 117.87, 117.73, 116.88, 116.73,75.90, 58.13, 43.42, 42.28, 28.06. HRMS [M+H]⁺ calcd for C₁₇H₁₈N₃O₄F₂:366.12655. found: 366.1269.

EXAMPLE 34

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-chlorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (4-chlorophenyl)methanamine.Pale pink solid. ¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.77 (1H, br), 7.33–7.35(2H, m), 7.25–7.28 (2H, m), 4.59 (2H, d, J=6.4 Hz), 4.04 (4H, ddd,J=14.0, 7.9, 2.7 Hz), 1.58 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm:168.12, 158.48, 151.87, 146.28, 135.72, 133.98, 129.92, 129.18, 129.09,125.90, 75.92, 58.12, 43.45, 42.61, 28.06. HRMS [M+H]⁺ calcd forC₁₇H₁₉N₃O₄Cl: 364.10642. found: 364.1060.

EXAMPLE 35

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,4-difluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (2,4-difluorophenyl)methanamine.Off white solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.86 (1H, t, J=5.6 Hz),7.34–7.40 (1H, m), 6.83–6.90 (2H, m), 4.62 (2H, d, J=6.4 Hz), 4.01–4.06(4H, m), 1.59 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 168.09, 158.43,151.81, 146.22, 131.30, 131.25, 131.22, 131.18, 125.87, 120.37, 120.34,111.85, 111.82, 111.68, 111.65, 104.47, 104.27, 104.07, 75.94, 58.12,43.43, 37.00, 28.07. HRMS [M+H]⁺ calcd for C₁₇H₁₈N₃O₄F₂: 366.12655.found: 366.1281.

EXAMPLE 36

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-chloro-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(2-chloro-4-fluorophenyl)methanamine. Off white solid, ¹H-NMR (500 MHz,CDCl₃) δ ppm: 8.05 (1H, br), 7.41 (1H, dd, J=8.4, 6.0 Hz), 7.17 (1H, dd,J=8.2, 2.4 Hz), 6.99 (1H, td, J=8.2, 2.7 Hz), 4.66 (2H, d, J=6.4 Hz),4.04 (4H, s), 1.60 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 167.88,163.30, 161.31, 158.70, 151.77, 146.08, 134.55, 134.47, 131.65, 131.58,130.70, 130.67, 126.12, 117.48, 117.28, 114.68, 114.51, 109.67, 75.99,58.10, 43.51, 40.82, 28.08. HRMS [M+H]⁺ calcd for C₁₇H₁₈N₃O₄FCl:382.09644. found: 382.0987.

EXAMPLE 37

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,4-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (2,4-dimethylphenyl)methanamine.Off white solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 12.08 (1H, brs), 7.63(1H, br), 7.15 (1H, d, J=7.6 Hz), 7.00–7.05 (2H, m), 4.57 (2H, d, J=5.8Hz), 4.01 (4H, s), 2.32 (3H, s), 2.32 (3H, s), 1.55 (6H, s). ¹³C-NMR(126 MHz, CDCl₃) δ ppm: 167.97, 157.98, 151.74, 146.35, 137.95, 136.22,131.90, 131.67, 128.38, 127.10, 125.64, 75.84, 58.21, 43.21, 41.15,28.07, 21.11, 19.13. HRMS [M+H]⁺ calcd for C₁₉H₂₄N₃O₄: 358.17669. found:358.1771.

EXAMPLE 38

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,5-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (3,5-dimethylphenyl)methanamine.Off white solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 12.09 (1H, s), 7.72–7.80(1H, br), 6.95 (1H, s), 6.94 (2H, s), 4.55 (2H, d, J=6.4 Hz), 4.00–4.04(4H, s), 2.32 (6H, s), 1.57 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm:168.19, 157.89, 151.73, 146.44, 138.71, 137.25, 129.58, 125.61, 125.48,75.86, 58.23, 43.18, 43.06, 28.08, 21.38. HRMS [M+H]⁺ calcd forC₁₉H₂₄N₃O₄: 358.17669. found: 358.1758.

EXAMPLE 39

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(4-fluoro-2-methylphenyl)methanamine. Off white solid, ¹H-NMR (500 MHz,CDCl₃) δ ppm: 11.97 (1H, s), 7.64 (1H, br), 7.23 (1H, dd, J=8.2, 5.8Hz), 6.87–6.94 (2H, m), 4.57 (2H, d, J=6.1 Hz), 4.02 (4H, s), 2.36 (3H,s), 1.56 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 168.07, 163.40,161.44, 157.82, 151.86, 146.43, 138.81, 138.75, 130.78, 130.75, 129.97,129.90, 125.42, 117.69, 117.52, 113.20, 113.03, 75.81, 58.23, 43.21,40.71, 28.09, 19.32. HRMS [M+H]⁺ calcd for C₁₈H₂₁N₃O₄F: 362.15162.found: 362.1521.

EXAMPLE 40

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-1-naphthalenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 37. White solid.¹H-NMR (500 MHz, CDCl₃) δ ppm: 12.00 (1H, s), 8.15–8.20 (1H, m), 8.05(1H, d, J=8.2 Hz), 7.73 (1H, br), 7.58–7.65 (2H, m), 7.43 (1H, dd,J=7.8, 5.3 Hz), 7.12 (1H, dd, J=10.1, 7.9 Hz), 5.02 (2H, d, J=6.1 Hz),3.99 (4H, ddd, J=13.8, 8.0, 2.9 Hz), 1.49 (6H, s). ¹³C-NMR (126 MHz,CDCl₃) δ ppm: 168.01, 160.13, 158.12, 157.77, 151.87, 146.51, 132.72,132.68, 128.59, 128.56, 127.86, 126.54, 126.46, 125.42, 124.45, 123.23,121.65, 121.60, 109.00, 108.84, 75.76, 58.21, 43.14, 40.86, 27.99. HRMS[M+H]⁺ calcd for C₂₁H₂₁N₃O₄F: 398.15162. found: 398.1536.

EXAMPLE 41

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2-methoxyphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(4-fluoro-2-methoxyphenyl)methanamine. HRMS [M+H]⁺ calcd for C₁₈H₂FN₃O₅:378.1465. found: 378.1480. Light yellow crystals; ¹H NMR (CDCl₃, 500MHz) δ ppm: 1.58 (6H, s, gem-di-Me), 3.88 (3H, s, OMe), 4.00 (4H, s,CH₂), 4.53 (2H, d, J=6.5 Hz, CH₂), 6.61–6.64 (2H, m, Ar—Hs), 7.24 (1H,m, Ar—Hs); ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm: 28.03 (CH₃), 38.79 (CH₂),43.09 (CH₂), 55.72 (CH₃), 58.27 (CH₂), 75.78 (C), 99.15, 99.35 (d, J=27Hz, CH), 106.97, 107.14 (d, J=21 Hz, CH), 121.17, 121.20 (d, J=3.8 Hz,C), 125.75 (C), 130.44, 130.51 (d, J=9.6 Hz, CH), 146.26 (C), 151.50(C), 157.87 (C═O), 158.77, 158.83 (d, J=9.6 Hz, C), 162.63, 164.48 (d,J=234 Hz, CF), 167.81 (C═O); HRMS (ESI) calcd for C₁₈H₂₁FN₃O₅ (M+H)378.1465. found 378.1480; UV (MeOH) λmax 219 nm (ε 1.66×10⁴), 245 (ε9.69×10³), 305 (ε 7.70×10³); Anal. Calcd for C₁₈H₂₀FN₃050.2H₂O: C,55.95; H, 5.48; N, 10.88. found C, 55.99; H, 5.11; N, 10.63.

EXAMPLES 42–43

Examples 42–43 can be prepared from intermediate 31, ethyl9,9-diethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the methods described for examples1, 19 and 20.

EXAMPLE 42

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from 4-fluorobenzylamine. ¹H NMR (500MHz, CDCl₃) δ ppm: 11.96 (1H, br), 7.76 (1H, br), 7.30 (2H, m), 7.06(2H, m), 4.58 (2H, d, J=6.4 Hz), 4.00, (4H, m), 1.93 (2H, m), 1.86 (2H,m), 0.86 (6H, t, J=7.3 Hz). ¹³C NMR (500 MHz, CDCl₃) δ ppm: 168.36,163.46, 157.87, 151.61, 143.23, 133.14, 129.50, 125.58, 115.99, 115.82,80.89, 58.46, 43.13, 42.50, 31.36, 7.79. HRMS [M+H]⁺ calcd forC₁₉H₂₃N₃O₄F: 376.16727. found: 376.1675.

EXAMPLE 43

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-).The title compound can be prepared from 3-methyl, 4-fluorobenzylamine.¹H NMR (500 MHz, CDCl₃) δ ppm: 11.99 (1H, br), 7.74 (1H, br), 7.15–7.09(2H, m), 6.99 (1H, m), 4.54 (2H, d, J=6.1 Hz), 4.00, (4H, m), 2.27 (1H,s), 1.93 (2H, m), 1.86 (2H, m), 0.84 (6H, t, J=7.3 Hz). ¹³C NMR (126MHz, CDCl₃) δ ppm: 168.32, 161.97, 160.02, 157.84, 151.56, 146.23,132.83, 130.96, 126.64, 125.59, 115.38, 80.88, 58.48, 43.11, 42.52,31.36, 14.66, 7.79. HRMS [M+H]⁺ calcd for C₂₀H₂₅N₃O₄F: 390.18292. found:390.1835.

EXAMPLES 44–45

Examples 44–45 can be prepared from intermediate 36,3-hydroxy-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylateand the indicated amines according to the methods described for examples1, 19 and 20.

EXAMPLE 44

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.The title compound can be prepared from 4-fluorobenzylamine ¹H NMR (500MHz, CDCl₃) δ ppm: 11.97 (1H, s), 7.72 (1H, br), 7.31 (1H, d, J=8.5 Hz),7.30 (1H, d, J=8.5 Hz), 7.05 (1H, t, J=8.5 Hz), 4.58 (2H, d, J=6.4 Hz),4.57 (2H, br), 3.67 (2H, t, J=6.4 Hz), 1.95 (2H, p, J=6.1 Hz), 1.57 (6H,s). ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.32, 163.45, 161.49, 158.20,153.63, 147.44, 133.17, 129.50, 129.43, 124.70, 115.97, 115.81, 82.29,60.87, 42.47, 38.68, 27.82, 27.30. HRMS [M+H]⁺ calcd for C₁₈H₂₁N₃O₄F:362.15162. found: 362.1530.

EXAMPLE 45

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.The title compound can be prepared from 3-methyl, 4-fluorobenzylamine.¹H NMR (500 MHz, CDCl₃) δ ppm: 12.00 (1H, s), 7.70 (1H, br), 7.14 (1H,m), 7.1 (1H, m), 6.98 (1H, t, J=8.9 Hz), 4.56 (2H, br), 4.54 (2H, d,J=6.4 Hz), 3.68 (2H, t, J=6.4 Hz), 2.27 (3H, s), 1.95 (2H, p, J=6.1 Hz),1.57 (6H, s). ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.26, 164.98, 160.02,158.22, 153.59, 147.44, 132.82, 130.97, 126.58, 125.46, 124.75, 115.38,82.30, 60.87, 42.51, 38.68, 27.83, 27.31, 14.66. HRMS [M+H]⁺ calcd forC₁₉H₂₃N₃O₄F: 376.16727. found: 376.1686.

EXAMPLES 46–51

Examples 46–52 can be prepared from the indicated intermediatesaccording to the method provide for example 46.

EXAMPLE 46

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[2-(4-morpholinyl)-2-oxoethoxy]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A solution of intermediate 157,3-benzyloxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-pyrimido[2,1-c][1,4]oxazine-2-carboxylicacid 4-fluoro-2-(2-morpholin-4-yl-2-oxo-ethoxy)-benzylamide, (187 mg,0.32 mmol) in trifluoroacetic acid (2 mL) was stirred at roomtemperature for 2.5 hrs, after which the mixture was concentrated invacuo to dryness. The residual oil was crystallized from 95% ethanol toprovide 120 mg (0.25 mmol, Yield 77%) of the title compound as a whitecrystalline powder: ¹H NMR (CDCl₃, 500 MHz) δ ppm: 1.57 (6H, s, Me),3.51, 3.64 (4H, brs, NCH₂), 3.70 (4H, m, OCH₂), 3.99 (4H, s, NCH₂,OCH₂), 4.60 (2H, d, J=6 Hz, NCH₂), 4.76 (2H, s, OCH₂), 6.59 (1H, dd,J=10, 2.5 Hz, Ar—H), 6.63 (1H, dt, J 2.5, 8 Hz, Ar—H), 7.29 (1H, dd,J=6.5, 8.5 Hz, Ar—H), 8.25 (1H, t, J=6 Hz, NH), 12.2 (br, OH). ¹³C NMR(CDCl₃, 125.77 Hz) δ ppm: 27.93 (CH₃), 38.44 (NCH₂), 42.39 (NCH₂), 43.14(NCH₂), 45.31 (NCH₂), 58.19 (OCH₂), 66.40 (OCH₂), 66.59, 66.86 (OCH₂),75.94 (C), 100.26, 100.46 (d, J=26 Hz, CH), 108.19, 108.36 (d, J=21 Hz,CH), 122.03, 122.06 (d, J=3 Hz, C), 125.84 (C), 131.06, 131.14 (d, J=11Hz, CH), 146.37 (C), 151.46 (C), 157.06, 157.14 (d, J=11 Hz, C), 157.96(C═O), 162.25, 164.21 (d, J=248 Hz, CF), 165.47 (C═O), 168.23 (C═O);HRMS calcd for C₂₃H₂₈N₄O₇F (M+H) 491.1942. found 491.1958; UV (MeOH)λmax 249 nm (ε 7.84×10³), 290 nm (ε 3.06×10³), 303 nm (ε 2.2×10³); Anal.Calcd for C₂₃H₂₇N₄O₇F.1.7H₂O: C, 53.01; H, 5.88; N, 10.75. found C,52.53; H, 5.37; N, 10.48.

EXAMPLE 47

Benzoic acid,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]-,methyl ester. The title compound can be prepared from intermediate 154,methyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoate.White solid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.94 (1H, br s), 8.76 (1H,t, J=6.77 Hz), 7.69 (1H, dd, J=9.2, 2.9 Hz), 7.53 (1H, dd, J=8.4, 5.5Hz), 7.15–7.22 (1H, m), 4.71 (2H, d, J=7.0 Hz), 3.97 (4H, s), 3.89–3.94(3H, m), 1.56 (6H, s); HRMS (ESI) calcd for C₁₉H₂₀FN₄O₆ (M+H) 406.1414.found 406.1432.

EXAMPLE 48

Benzoic acid,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]-.The title compound can be prepared from intermediate 190,2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoicacid. White solid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.92 (1H, br s), 8.68(1H, t, J=6.4 Hz), 7.80 (1H, dd, J=8.7, 2.6 Hz), 7.60 (1H, dd, J=8.5,5.5 Hz), 7.30 (1H, dt, J=8.1, 2.8 Hz), 4.78 (2H, d, J=6.7 Hz), 4.00 (4H,s), 1.58 (6H, s); HRMS (ESI) calcd for C₁₈H₁₈FN₃O₆(M+H) 392.1258. found392.1250.

EXAMPLE 49

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 143,N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (500 MHz, DMSO-d₆) δ ppm: 11.97 (1H, br s), 9.46 (1H, br s),8.55–8.51 (1H, m), 7.40–7.38 (1H, m), 7.32–7.27 (2H, m), 4.56 (2H, d,J=6.1 Hz), 3.97 (2H, t, J=4.9 Hz), 3.82 (2H, t, J=4.9 Hz), 2.80 (3H, d,J=4.6 Hz), 1.55 (6H, s). HRMS (M+H) calcd for C₁₉H₂₂FN₄O₅: 405.1574.found: 405.1588.

EXAMPLE 50

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(cyclopropylamino)carbonyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 155,N-(2-(cyclopropylcarbamoyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.White solid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.98 (1H, br s), 8.84 (1H,t, J=7.32 Hz), 7.48 (1H, dd, J=9.0, 5.3 Hz), 7.05–7.16 (2H, m),6.20–6.31 (1H, br s), 4.56 (2H, d, J=6.6 Hz), 3.92–4.02 (4H, m), 2.90(1H, dt, J=7.1, 3.3 Hz), 1.59 (6H, s), 0.88 (2H, q, J=6.6 Hz), 0.57–0.66(2H, m); HRMS (ESI) calcd for C₂₁H₂₃FN₄O₅ (M+H) 431.1731. found431.1734.

EXAMPLE 51

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[[(2-hydroxyethyl)amino]carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 191,N-(2-((2-aminoethyl)carbamoyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (500 MHz, CDCl₃) δ ppm: 11.98 (1H, br s), 8.88 (1H, t, J=6.0 Hz),7.51 (1H, dd, J=8.2, 5.5 Hz), 7.21 (1H, dd, J=8.5, 2.8 Hz), 7.14 (1H,dt, J=8.3, 2.6 Hz), 6.57–6.63 (1H, m), 4.58 (2H, d, J=6.7 Hz), 4.00 (4H,s), 3.87 (2H, t, J=5.1 Hz), 3.63–3.68 (2H, m), 1.60 (6H, s); HRMS (ESI)calcd for C₂₀H₂₃FN₄O₆ (M+H) 435.1680. found 435.1700.

EXAMPLE 52

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(4-morpholinylcarbonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 156,N-(4-fluoro-2-(morpholine-4-carbonyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.White solid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.94 (1H, s), 8.46 (1H, t,J=5.5 Hz), 7.47 (1H, dd, J=8.5, 5.5 Hz), 7.10 (1H, dt, J=8.4, 2.4 Hz),6.94 (1H, dd, J=8.2, 2.4 Hz), 4.00 (4H, s), 3.79–3.88 (2H, br), 3.78(2H, br), 3.61 (2H, br), 3.31–3.40 (2H, br), 1.61 (6H, s); HRMS (ESI)calcd for C₂₂H₂₅FN₄O₆ (M+H) 461.1836. found 461.1852.

EXAMPLE 53–60

Examples 53–60 can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the method described for thesynthesis of examples 1, 19 and 20.

EXAMPLE 53

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1H-imidazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 89. ¹H-NMR (500MHz, CDCl₃) δ ppm: 11.66 (1H, bs), 8.07 (1H, s), 7.74 (1H, t, J=5.5 Hz),7.57 (1H, dd, J=8.7, 5.9 Hz), 7.35 (1H, s), 7.25–7.21 (2H, m), 7.08 (1H,dd, J=8.2, 2.4 Hz), 4.42 (2H, d, J=6.4 Hz), 4.01 (4H, s), 1.59 (6H, s).HRMS [M+H]⁺ calcd for C₂₀H₂₁N₅O₄F: 414.15777. found: 414.1563. Analcalcd for C₂₀H₂₀N₅O₄F.0.25H₂O: C, 57.48; H, 4.94; N, 16.76; F, 4.55.found: C, 57.77; H, 4.89; N, 16.29; F, 4.48.

EXAMPLE 54

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[S-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-e.The title compound can be prepared from intermediate 97. ¹H NMR (500MHz, CDCl₃) δ ppm: 11.82 (1H, s), 8.70 (1H, t, J=6.5 Hz), 8.39 (1H, s),8.17 (1H, s), 7.40 (1H, dd, J 8.6, 2.7 Hz), 7.34 (1H, dd, J=8.9, 4.9Hz), 7.17–7.13 (1H, m), 4.44 (2H, d, J=6.7 Hz), 4.01 (4H, s), 1.62 (6H,s). HRMS (M+H) calcd for C₁₉H₂₀FN₆O₄: 415.1530. found: 415.1544. Analcalcd for C₁₉H₁₉FN₆O₄: C, 55.07; H, 4.62; N, 20.28; F, 4.58. found: C,54.83; H, 4.51; N, 19.89; F, 4.56.

EXAMPLE 55

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[3-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 93. White solid.36% yield. ¹H-NMR (500 MHz, CDCl₃) δ ppm: 11.96 (1H, s), 8.42–8.39 (2H,m), 7.14–7.11 (1H, m), 4.97 (1H, dd J=14.3, 8.8 Hz), 4.37 (1H, dd,J=14.3, 4.0 Hz), 4.00 (4H, s), 3.86–3.80 (1H, m), 3.75–3.70 (1H, m),3.34–3.24 (2H, m), 2.44–2.39 (2H, m), 2.08–2.00 (1H, m), 1.83–1.77 (1H,m), 1.60 (3H, s), 1.57 (3H, s). HRMS [M+H]⁺ calcd for C₂₁H₂₆N₄O₆FS:481.15572. found: 481.1559. Anal calcd for C₂₁H₂₅N₄O₆FS: C, 52.49; H,5.24; N, 11.66; S, 6.67; F, 3.95. found: C, 52.43; H, 5.21; N, 11.61; S,6.56; F, 4.16.

EXAMPLE 56

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[3-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 95. White solid.¹H-NMR (500 MHz, CDCl₃) δ ppm: 11.86 (1H, s), 8.76 (1H, brs), 8.46 (1H,d, J=3.0 Hz), 8.22 (1H, s), 7.48–7.47 (2H, m), 7.29–7.26 (1H, m), 4.44(2H, d, J=6.7 Hz), 4.01 (4H, s), 1.63 (6H, s). HRMS [M+H]⁺ calcd forC₁₉H₂₀N₆O₄F: 415.15302. found: 415.1541. Anal calcd for C₁₉H₁₉N₆O₄F: C,55.07; H, 4.62; N, 20.28; F, 4.58. found: C, 55.18; H, 4.42; N, 20.17;F, 4.51.

EXAMPLE 57

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 77. Pale orangesolid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.99 (1H, s), 8.99 (1H, t, J=6.4Hz), 7.91 (2H, s), 7.65–7.58 (2H, m), 7.10 (1H, td, J=8.1, 2.6 Hz), 4.61(2H, d, J=7.0 Hz), 3.97 (4H, s), 1.55 (6H, s). HRMS [M-H]⁻ calcd forC₁₉H₁₈N₆O₄F: 413.13736. found: 413.1354. Anal calcd for C₁₉H₁₇N₆O₄F: C,55.07; H, 4.62; N, 20.28; F, 4.58. found: C, 54.94; H, 4.78; N, 20.32;F, 4.53.

EXAMPLE 58

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 77. Pale brownsolid ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.85 (1H, s), 7.88–7.82 (3H, m),7.79 (2H, s), 7.47 (1H, t, J=8.3 Hz), 4.67 (2H, d, J=6.2 Hz), 3.99 (4H,s), 1.56 (6H, s). HRMS [M+H]⁺ calcd for C₁₉H₂₀N₆O₄F: 415.15302. found:415.1513. Anal calcd for C₁₉H₁₉N₆O₄F: C, 55.07; H, 4.62; N, 20.28; F,4.58. found: C, 54.94; H, 4.76; N, 19.94; F, 4.26.

EXAMPLE 59

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-bromo-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(2-bromo-4-fluorophenyl)methanamine. White needles. ¹H-NMR (300 MHz,CDCl₃) δ ppm: 11.78 (1H, s), 8.08 (1H, t, J=6.0 Hz), 7.39 (1H, dd,J=8.8, 5.8 Hz), 7.31 (1H, dd, J=8.0, 2.6 Hz), 7.01 (1H, dt, J=8.2, 2.6Hz), 4.61 (2H, d, J=6.6 Hz), 3.99 (4H, s), 1.56 (6H, s). HRMS [M+H]⁺calcd for C₁₇H₁₈N₃O₄FBr: 426.04648. found: 426.0465.

EXAMPLE 60

1H-1,2,4-Triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,methyl este. The title compound can be prepared from intermediate 91.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.90 (1H, s), 8.49 (1H, s),8.36 (1H, t, J=6.2 Hz), 7.72 (1H, dd, J=8.8, 5.9 Hz), 7.26–7.20 (1H, m),7.14 (1H, dd, J=8.4, 2.6 Hz), 4.49 (2H, d, J=6.6 Hz), 4.01 (3H, s), 3.98(4H, s), 1.58 (6H, s). HRMS [M+H]⁺ calcd for C₂₁H₂₂N₆O₆F: 473.1585.found: 473.1563. Anal calcd for C₂₁H₂₁N₆O₆F.0.5H₂O: C, 52.39; H, 4.61;N, 17.46; F, 3.95. found: C, 52.14; H, 4.70; N, 17.41; F, 4.12.

EXAMPLE 61

1H-1,2,4-Triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-.To a solution of example 60, 1H-1,2,4-triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,methyl ester, (2.156 g, 4.6 mmol) in tetrahydrofuran (200 mL) and water(50 mL) at 0° C. was added lithium hydroxide monohydrate (0.58 g, 13.8mmol). The mixture was stirred at 0° C. 2 h and at room temp for 1 h.The resulting solution was partitioned between ethyl acetate and water.The aqueous phase was acidified with 1 N HCl and extracted with ethylacetate and CH₂Cl₂. The organic extracts were combined, dried (Na₂SO₄)and concentrated to give the title compound as a white solid (2.05 g,97% yield). ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.91 (1H, bs), 8.55 (1H, s),8.43 (1H, t, J=6.6 Hz), 7.77 (1H, dd, J=8.8, 5.9 Hz), 7.28–7.23 (1H, m),7.16 (1H, dd, J=8.0, 2.6 Hz), 4.47 (2H, d, J=6.9 Hz), 3.98 (4H, s), 1.59(6H, s). HRMS [M+H]⁺ calcd for C₂₀H₂₀N₆O₆F: 459.14285. found: 459.1442.

EXAMPLES 62–72

Examples 62–72 can be prepared from intermediate 61,1H-1,2,4-triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,according to the method described for the synthesis of example 62.

EXAMPLE 62

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-(4-morpholinylcarbonyl)-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To a solution of example 61, 1H-1,2,4-triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,(0.0259 g, 0.057 mmol) in DMF (2 mL), at 0° C., was addedO-(7-azabenzotriazol-1-yl)-N,N,N¹,N¹-tetramethyluroniumhexafluorophosphate (0.044 g, 0.115 mmol). The solution was stirred at0° C. for 10 min before adding morpholine (0.025 mL, 0.285 mmol) afterwhich it was stirred at room temp for 2 h. Purification by reverse phasepreparative HPLC chromatography (YMC Combiprep ODS-A, 30 mm×50 mm,MeOH/H₂O/0.1% CF₃CO₂H) gave the title compound as a white solid (0.015g, 50% yield). ¹H-NMR (500 MHz, CDCl₃) δ ppm: 8.50 (1H, t, J=6.9 Hz),8.45 (1H, s), 7.69 (1H, dd, J=8.7, 5.9 Hz), 7.22 (1H, td, J=8.2, 2.3Hz), 7.13 (1H, dd, J=8.2, 2.4 Hz), 4.49 (2H, s), 3.98 (4H, s), 3.88–3.72(8H, m), 1.57 (6H, s). HRMS [M+H]⁺ calcd for C₂₄H₂₇N₇O₆F: 528.20069.found: 528.2025.

EXAMPLE 63

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-[(dimethylamino)carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Pale purple solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.51–8.45 (2H, m),7.70 (1H, dd, J=8.4, 5.9 Hz), 7.24–7.18 (1H, m), 7.12 (1H, dd, J=8.2,2.4 Hz), 4.47 (2H, d, J=6.9 Hz), 3.97 (4H, s), 3.24 (3H, s), 3.15 (3H,s), 1.54 (6H, s). HRMS [M+H]⁺ calcd for C₂₂H₂₅N₇O₅F: 486.19013. found:486.1887.

EXAMPLE 64

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[[(methylsulfonyl)amino]carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.52 (1H, s), 8.36 (1H, t,J=6.8 Hz), 7.70 (1H, dd, J=8.6, 5.7 Hz), 7.26–7.19 (1H, m), 7.13 (1H,dd, J=8.4, 2.6 Hz), 4.46 (2H, d, J=7.0 Hz), 3.95 (4H, s), 3.39 (4H, s),1.57 (6H, s). HRMS [M+H]⁺ calcd for C₂₁H₂₃N₇O₇FS: 536.1364. found:536.1376. Anal calcd for C₂₁H₂₂N₇O₇FS.0.07CF₃CO₂H: C, 46.72; H, 4.09; N,18.04; F, 4.23. found: C, 46.42; H, 3.91; N, 17.70; F, 4.17.

EXAMPLE 65

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[(1R)-2-hydroxy-1-phenylethyl]-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.43 (1H, s), 8.20 (1H, t,J=6.0 Hz), 7.64 (1H, dd, J=8.8, 5.9 Hz), 7.42–7.40 (1H, m), 7.26–7.19(1H, m), 7.11 (1H, dd, J=8.0, 2.6 Hz), 4.53 (2H, d, J=6.6 Hz), 3.99 (4H,s), 3.06 (3H, d, J=4.7 Hz), 1.56 (6H, s). HRMS [M+H]⁺ calcd forC₂₁H₂₃N₇O₅F: 472.1745. found: 472.1741. Anal calcd for C₂₁H₂₂N₇O₅F: C,53.50; H, 4.70; N, 20.79; F, 4.03. found: C, 53.22; H, 4.51; N, 20.70;F, 4.01.

EXAMPLE 66

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-[(4-acetyl-1-piperazinyl)carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.46 (1H, s), 8.36 (1H, t,J=5.7 Hz), 7.68 (1H, dd, J=8.6, 5.7 Hz), 7.27–7.21 (1H, m), 7.14 (1H,dd, J=8.2, 2.7 Hz), 4.48 (2H, d, J=6.6 Hz), 3.98 (4H, s), 3.94–3.61 (8H,m), 2.13 (3H, s), 1.55 (6H, s). HRMS [M+H]⁺ calcd for C₂₆H₃₀N₈O₆F:569.2272. found: 569.2269. Anal calcd for C₂₆H₂₉N₈O₆F.0.8H₂O: C, 53.57;H, 5.29; N, 19.22; F, 3.26. found: C, 53.48; H, 4.95; N, 19.21; F, 3.21.

EXAMPLE 67

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[[(2-hydroxyethyl)methylamino]carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.54 (1H, t, J=7.3 Hz), 8.44(1H, s), 7.66 (1H, dd, J=8.8, 5.8 Hz), 7.21–7.09 (2H, m), 4.44 (2H, d,J=4.4 Hz), 3.93 (4H, s), 3.86–3.78 (2H, m), 3.70–3.65 (2H, m), 3.13 (3H,s), 1.94 (1H, bs), 1.55 (6H, s). HRMS [M+H]⁺ calcd for C₂₃H₂₇N₇O₆F:516.2007. found: 516.2011. Anal calcd for C₂₃H₂₆N₇O₆F: C, 53.59; H,5.08; N, 19.02; F, 3.68. found: C, 53.31; H, 5.06; N, 18.80; F, 3.60.

EXAMPLE 68

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[[[(4-fluorophenyl)sulfonyl]amino]carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.47 (1H, s), 8.18–8.13 (2H,m), 7.68 (1H, dd, J=8.8, 5.9 Hz), 7.24–7.16 (3H, m), 7.08 (1H, dd,J=8.0, 2.6 Hz), 4.39 (2H, s), 3.96 (4H, s), 1.55 (6H, s). HRMS [M+H]⁺calcd for C₂₆H₂₄N₇O₇F₂S: 616.1426. found: 616.1426. Anal calcd forC₂₆H₂₃N₇O₇F₂S: C, 50.73; H, 3.76; N, 15.92; F, 6.17. found: C, 50.49; H,3.66; N, 15.98; F, 6.12.

EXAMPLE 69

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[(4-methyl-1-piperazinyl)carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Pale brown foam. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.43 (1H, s), 8.29 (1H,t, J=6.8 Hz), 7.63 (1H, dd, J=8.4, 5.9 Hz), 7.25–7.19 (1H, m), 7.11 (1H,dd, J=8.0, 2.6 Hz), 4.46 (2H, d, J=6.6 Hz), 3.95 (4H, s), 3.30 (4H, bs),2.86 (3H, s), 1.91 (4H, bs), 1.53 (6H, s). HRMS [M+H]⁺ calcd forC₂₅H₃₀N₈O₅F: 541.2323. found: 541.2341. Anal calcd forC₂₅H₂₉N₈O₅F.0.5CF₃CO₂H.0.5H₂O: C, 46.67; H, 4.41; N, 15.55; F, 14.50.found: C, 46.86; H, 4.44; N, 15.67; F, 14.48.

EXAMPLE 70

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-[[[2-(dimethylamino)ethyl]amino]carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Pale brown foam. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.39 (1H, s), 7.58 (1H,dd, J=8.6, 5.7 Hz), 7.23–7.14 (1H, m), 7.09 (1H, dd, J=8.4, 2.6 Hz),4.50 (2H, s), 3.95 (4H, s), 3.84 (2H, t, J=5.5 Hz), 3.34 (2H, t, J=6.0Hz), 2.89 (6H, s), 1.55 (6H, s). HRMS [M+H]⁺ calcd for C₂₄H₃₀N₈O₅F:529.2323. found: 529.2315.

EXAMPLE 71

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-[[[2-(dimethylamino)ethyl]methylamino]carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Pale brown foam. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.44 (1H, s), 8.21 (1H,t, J=6.5 Hz), δ 7.67–7.58 (1H, m), 7.24–7.09 (2H, m), 4.48–4.45 (2H, m),3.95 (4H, s), 3.94–3.89 (2H, m), 3.37–3.33 (2H, m), 2.91 (6H, s), 2.88(3H, s), 1.56 (6H, s). HRMS [M+H]⁺ calcd for C₂₅H₃₂N₈O₅F: 543.2480.found: 543.2491. Anal calcd for C₂₅H₃₁N₈O₅F.CF₃CO₂H: C, 45.20; H, 4.32;N, 14.54; F, 17.26. found: C, 45.13; H, 4.14; N, 14.74; F, 17.01.

EXAMPLE 72

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[[(2-hydroxyethyl)amino]carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.41 (1H, s), 8.32 (1H, t,J=6.2 Hz), 7.63 (1H, dd, J=8.4, 5.9 Hz), 7.20 (1H, dt, J=8.4, 2.6 Hz),7.11 (1H, dd, J=8.4, 2.6 Hz), 4.52–4.50 (2H, m), 3.95 (4H, s), 3.78 (2H,t, J=5.1 Hz), 3.59 (2H, t, J=5.1 Hz), 1.56 (6H, s). HRMS [M+H]⁺ calcdfor C₂₂H₂₅N₇O₆F: 502.1850. found: 502.1850.

EXAMPLE 73

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2-iodophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 4.05 (4H, s, 2×CH₂),4.63 (2H, d, J=7.1 Hz, NCH₂), 7.11 (1H, m, aromatic), 7.42 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 7.62 (1H, dd, J=2.5 Hz and J=8.1 Hz,aromatic), 8.20 (1H, broad t, NH), 11.82 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₇H₁₈FIN₃O₄ [M+H⁺]: 474.0326. found: 474.0328.

EXAMPLES 74–77

Examples 74–77 can be prepared from the indicated intermediates byhydrogenolysis or trifluoroacetic acid mediated hydrolysis.

EXAMPLE 74

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(5-fluoro[1,1′-biphenyl]-2-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 176,N-(4-fluoro-2-phenyl-benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.56 (6H, s, 2×CH₃), 4.03 (4H, s, 2×CH₂),4.56 (2H, d, J=6.0 Hz, NCH₂), 7.03 (1H, dd, J=2.5 Hz and J=9.3 Hz,aromatic), 7.09 (1H, m, aromatic), 7.36 (2H, m, aromatics), 7.42–7.51(5H, m, aromatics and NH), 11.96 (1H, s, OH). HRMS (ESI⁺) calculated forC₂₃H₂₃FN₃O₄ [M+H⁺]: 424.1673. found: 424.1675.

EXAMPLE 75

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.57 (6H, s, 2×CH₃), 4.04 (4H, s, 2×CH₂),4.55 (2H, d, J=6.1 Hz, NCH₂), 7.04 (1H, dd, J=2.5 Hz and J=9.1 Hz,aromatic), 7.16 (1H, m, aromatic), 7.43 (1H, m, aromatic), 7.49 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 7.52 (1H, broad t, NH), 7.71 (1H, m,aromatic), 8.63 (1H, m, aromatic), 8.70 (1H, m, aromatic), 11.84 (1H, s,OH). HRMS (ESI⁺) calculated for C₂₂H₂₂FN₄O₄ [M+H⁺]: 425.1625. found:425.1616.

EXAMPLE 76

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-methoxy-3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Hydrogenolysis of intermediate 175,N-(4-fluoro-2-(2-methoxypyridin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamidegave the title material as a white solid; mp 227° C. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.58 (6H, s, 2×CH₃), 3.99 (3H, s, OCH₃), 4.04 (4H, s,2×CH₂), 4.43 (2H, broad, NCH₂), 6.97 (1H, dd, J=2.5 Hz and J=8.5 Hz,aromatic), 7.03 (1H, dd, J=5.0 Hz and J=8.5 Hz, aromatic), 7.12 (1H, m,aromatic), 7.45 (1H, dd, J=4.5 Hz and J=8.6 Hz, aromatic), 7.53 (1H, dd,J=2.0 Hz and J=7.1 Hz, aromatic), 7.57 (1H, broad t, NH), 8.28 (1H,dd,J=2.5 Hz and J=5.0 Hz, aromatic), 12.03 (1H, s, OH). HRMS (ESI⁺)calculated for C₂₃H₂₄FN₄O₅ [M+H⁺]: 455.1731. found: 455.1737.

EXAMPLE 77

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(6-methoxy-3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.58 (6H, s, 2×CH₃), 4.02 (3H, s, OCH₃),4.04 (4H, s, 2×CH₂), 4.55 (2H, d, J=6.1 Hz, NCH₂), 6.87 (1H, d, J=9.0Hz, aromatic), 7.01 (1H, dd, J=2.0 Hz and J=9.0 Hz, aromatic), 7.12 (1H,m, aromatic), 7.46 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.55 (1H,broad t, NH), 7.60 (1H, dd, J=2.0 Hz and J=8.6 Hz, aromatic), 8.17 (1H,d, J=2.0 Hz, aromatic), 11.89 (1H, s, OH). HRMS (ESI⁺) calculated forC₂₃H₂₄FN₄O₅ [M+H⁺]: 455.1731. found: 455.1717.

EXAMPLES 78–80

Examples 78–80 can be prepared from the indicated intermediatesaccording to the method described for example 78.

EXAMPLE 78

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1,2-dihydro-2-oxo-3-pyridinyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-. A solution of intermediate 175,N-(4-fluoro-2-(2-methoxypyridin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.125 g, 0.23 mmol) in acetonitrile (5 ml) was treated with sodiumiodide (0.090 g, 0.6 mmol) and chlorotrimethylsilane (0.45 ml, 3.5mmol), sealed in a pressure resistant vessel and heated at 80° C. for1.5 h. The mixture was diluted with ethyl acetate washed with water andbrine then dried over anhydrous magnesium sulfate. Filtration andremoval of solvent provided the title compound. ¹HNMR 400 MHz (CDCl₃) δppm: 1.60 (6H, s, 2×CH₃), 4.03 (4H, s, 2×CH₂), 4.5 (2H, broad, NCH₂),6.47 (1H, m, aromatic), 6.95 (1H, dd, J=2 Hz and J=9 Hz, aromatic), 7.12(1H, m, aromatic), 7.45 (1H, dd, J=2 Hz and J=7 Hz, aromatic), 7.50 (1H,dd, J=6 Hz and J=9 Hz, aromatic), 7.53 (1H, dd, J=2 Hz and J=7 Hz,aromatic), 8.64 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₂H₂₂FN₄O₅ [M+H⁺]: 441.1574. found: 441.1585.

EXAMPLE 79

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1,6-dihydro-6-oxo-3-pyridinyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from example 77. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.59 (6H, s, 2×CH₃), 4.02 (3H, s, OCH₃), 4.05 (4H, s,2×CH₂), 4.55 (2H, d, J=6.6 Hz, NCH₂), 6.95 (1H, d, J=9.0 Hz, aromatic),7.00 (1H, dd, J=2.6 Hz and J=9.0 Hz, aromatic), 7.17 (1H, m, aromatic),7.46 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.63 (1H, d, J=2.6 Hz,aromatic), 7.71 (1H, broad t, NH), 7.79 (1H, dd, J=2.6 Hz and J=9.1 Hz,aromatic). HRMS (ESI⁺) calculated for C₂₂H₂₂FN₄O₅ [M+H⁺]: 441.1574.found: 441.1570.

EXAMPLE 80

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1,6-dihydro-6-oxo-2-pyridinyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared fromN-(4-fluoro-2-(6-methoxypyridin-2-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,which can be prepared according to the methods described for thesynthesis of intermediate 175. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.62 (6H,s, 2×CH₃), 4.04 (4H, s, 2×CH₂), 4.60 (2H, d, J=7.0 Hz, NCH₂), 6.38 (1H,d, J=7.0 Hz, aromatic), 6.68 (1H, d, J=9.0 Hz, aromatic), 7.14 (1H, dd,J=2.5 Hz and J=9.1 Hz, aromatic), 7.23 (1H, m, aromatic), 7.50 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 7.58 (1H, dd, J=7.0 Hz and J=9.0 Hz,aromatic), 8.15 (1H, broad t, NH).

EXAMPLES 81–93

Examples 81–93 can be prepared from the indicated intermediates byhydrogenolysis or trifluoroacetic acid mediated hydrolysis.

EXAMPLE 81

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 152,N-(4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide¹HNMR 400 MHz (CDCl₃) δ ppm: 1.64 (6H, s, 2×CH₃), 2.59 (3H, s, CH₃),4.04 (4H, s, 2×CH₂), 4.50 (2H, d, J=7.1 Hz, NCH₂), 7.1 (1H, dd, J=2.5 Hzand J=8.6 Hz, aromatic), 7.20 (1H, m, aromatic), 7.72 (1H, dd, J=6.0 Hzand J=8.6 Hz, aromatic), 8.34 (1H, s, CH), 8.80 (1H, broad t, NH), 12.11(1H, s, OH). HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄ [M+H⁺]: 429.1687.found: 429.1675.

EXAMPLE 82

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.66 (6H, s, 2×CH₃), 2.50 (3H, s, CH₃),4.04 (4H, s, 2×CH₂), 4.32 (2H, d, J=7.0 Hz, NCH₂), 7.05 (1H, dd, J=2.5Hz and J=8.1 Hz, aromatic), 7.27 (1H, m, aromatic), 7.70 (1H, dd, J=6.1Hz and J=8.6 Hz, aromatic), 8.04 (1H, s, CH), 8.61 (1H, broad t, NH),11.90 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄ [M+H⁺]:429.1687. found: 429.1688.

EXAMPLE 83

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 153,N-(2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.61 (6H, s, 2×CH₃), 2.51 (3H, s, CH₃),4.05 (4H, s, 2×CH₂), 4.72 (2H, d, J=6.6 Hz, NCH₂), 7.44–7.55 (3H, m,aromatics), 7.94 (1H, broad t, NH), 8.46 (1H, s, CH), 11.86 (1H, s, OH).HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄ [M+H⁺]: 429.1687. found:429.1695.

EXAMPLE 84

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1,2,3-thiadiazol-4-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 172,N-(4-fluoro-2-(1,2,3-thiadiazol-4-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (DMSO-d₆) δ ppm: 1.54 (6H, s, 2×CH₃), 3.83 (2H, broad t,CH₂), 3.96 (2H, broad t, CH₂), 4.61 (2H, d, J=6.7 Hz, NCH₂), 7.39 (1H,m, aromatic), 7.55 (1H, m, aromatic), 7.62 (1H, m, aromatic), 9.41 (1H,broad t, NH), 9.63 (1H, s, CH), 12.0 (1H, s, OH). HRMS (ESI⁺) calculatedfor C₁₉H₁₉FN₅O₄S [M+H⁺]: 432.1142. found: 432.1124.

EXAMPLE 85

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1H-pyrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 177,N-(4-fluoro-2-(1H-pyrazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.59 (6H, s, 2×CH₃), 4.03 (4H, s, 2×CH₂),4.67 (2H, d, J=6.6 Hz, NCH₂), 6.65 (1H, d, J=2.5 Hz, CH), 7.07 (1H, m,aromatic), 7.31 (1H, dd, J=2.5 Hz and J=9.8 Hz, aromatic), 7.56 (1H, dd,J=5.8 Hz and J=8.3 Hz, aromatic), 7.75 (1H, d, J=2.5 Hz, CH), 9.22 (1H,broad t, NH), 10.33 (1H, broad, NH), 12.2 (1H, s, OH). HRMS (ESI⁺)calculated for C₂₀H₂₁FN₅O₄ [M+H⁺]: 414.1578. found: 414.1560.

EXAMPLE 86

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(5-methyl-2-oxazolyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 173,N-(4-fluoro-2-(5-methyloxazol-2-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.58 (6H, s, 2×CH₃), 2.48 (3H, s, CH₃),4.01 (4H, s, 2×CH₂), 4.77 (2H, d, J=7.0 Hz, NCH₂), 6.96 (1H, s, CH),7.13 (1H, m, aromatic), 7.61 (1H, dd, J=5.8 Hz and J=8.3 Hz, aromatic),7.70 (1H, dd, J=3.2 Hz and J=9.6 Hz, aromatic), 9.76 (1H, broad t, NH),12.15 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₂FN₄O₅ [M+H⁺]:429.1574. found: 429.1564.

EXAMPLE 87

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(ethylamino)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 170,N-(2-(ethylamino)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.30 (3H, t, J=7.3 Hz, CH₃), 1.59 (6H, s,2×CH₃), 3.12 (2H, m, CH₂), 4.04 (4H, s, 2×CH₂), 4.52 (2H, d, J=6.6 Hz,NCH₂), 5.09 (1H, broad, NH), 6.3–6.37 (2H, m, aromatics), 7.10 (1H, dd,J=6.6 Hz and J=8.1 Hz, aromatic), 7.67 (1H, broad t, NH), 11.93 (1H, s,OH). HRMS (ESI⁺) calculated for C₁₉H₂₄FN₄O₄ [M+H⁺]: 391.1782. found:391.1774.

EXAMPLE 88

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-ethynyl-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 179,N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.61 (6H, s, 2×CH₃), 3.46 (1H, s, CH), 4.04(4H, s, 2×CH₂), 4.73 (2H, d, J=6.5 Hz, NCH₂), 7.1 (1H, m, aromatic),7.26 (1H, dd, J=2.5 Hz and J=8.5 Hz, aromatic), 7.40 (1H, dd, J=5.6 Hzand J=8.6 Hz, aromatic), 8.18 (1H, broad t, NH), 11.92 (1H, s, OH). HRMS(ESI⁺) calculated for C₁₉H₁₉FN₃O₄ [M+H⁺]: 372.1360. found: 372.1345.

EXAMPLE 89

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-hydroxy-1-propynyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 182,N-(4-fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.60 (6H, s, 2×CH₃), 4.04 (4H, s, 2×CH₂),4.55 (2H, broad d, CH₂), 4.73 (2H, d, J=6.6 Hz, NCH₂), 7.07 (1H, m,aromatic), 7.20 (1H, dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.38 (1H, dd,J=5.3 Hz and J=8.3 Hz, aromatic), 7.95 (1H, broad t, NH), 11.90 (1H, s,OH). HRMS (ESI⁺) calculated for C₂₀H₂₁FN₃O₅ [M+H⁺]: 402.1465. found:402.1463.

EXAMPLE 90

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[(methylsulfonyl)oxy]-1-propynyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 183,3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynylmethanesulfonate. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.62 (6H, s, 2×CH₃), 3.16(3H, s, CH₃), 4.05 (4H, s, 2×CH₂), 4.72 (2H, d, J=6.0 Hz, NCH₂), 5.12(2H, s, OCH₂), 7.12 (1H, m, aromatic), 7.21 (1H, dd, J=2.6 Hz and J=8.6Hz, aromatic), 7.45 (1H, dd, J=5.1 Hz and J=8.6 Hz, aromatic), 8.03 (1H,broad t, NH).

EXAMPLE 91

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-(dimethylamino)-1-propynyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 184,N-(2-(3-(dimethylamino)prop-1-ynyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound was isolated as a trifluoroacetic acid salt. ¹HNMR400 MHz (CDCl₃) δ ppm: 1.62 (6H, s, 2×CH₃), 3.03 (6H, s, 2×CH₃), 4.06(4H, s, 2×CH₂), 4.23 (2H, s, NCH₂), 4.75 (2H, d, J=6.0 Hz, NCH₂), 7.16(1H, m, aromatic), 7.24 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.42(1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.04 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₂H₂₆FN₄O₄ [M+H⁺]: 429.1938. found: 429.1917.

EXAMPLE 92

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-(methylsulfonyl)-1-propynyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 186,N-(4-fluoro-2-(3-(methylsulfonyl)prop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 3.16 (3H, s, SCH₃),4.04 (4H, s, 2×CH₂), 4.17 (2H, s, SCH₂), 4.70 (2H, d, J=6.0 Hz, NCH₂),7.12 (1H, m, aromatic), 7.21 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic),7.49 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.16 (1H, broad t, NH).,11.99 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₃FN₃O₆S [M+H⁺]:464.1292. found: 464.1271.

EXAMPLE 93

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)-1-propynyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 1.86 (2H, m, CH₂),2.28 (2H, m, CH₂), 3.11 (2H, m, CH₂), 3.53 (2H, m, CH₂), 4.05 (4H, s,2×CH₂), 4.27 (2H, s, NCH₂), 4.73 (2H, d, J=6.0 Hz, NCH₂), 7.07 (1H, m,aromatic), 7.17 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.47 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 8.12 (1H, broad t, NH).

EXAMPLE 94

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[2-(phenylsulfonyl)ethyl]-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand 7-(aminomethyl)indolin-2-one according to the methods described forexamples 1, 19 and 20. ¹H NMR (500 MHz, DMSO-d₆) δ ppm: 1.58 (s, 6),3.50 (s, 2), 3.83 (m, 2), 3.97 (m, 2), 4.42 (d, 2), 6.9–7.13(overlapping m, 3). Anal calcd C₁₉H₂₀N₄O₅: C, 59.36; H, 5.24; N, 14.57.Found: C, 59.61; H, 5.43; N, 14.46.

EXAMPLE 95

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2-hydroxyphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A solution of intermediate 144,N-(4-fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.070 g, 0.154 mmol) in dichloromethane (3 mL) and trifluoroacetic acid(3 mL) was stirred for 2 hours. The solvent was then removed in vacuoand the resulting residue dissolved in ethyl acetate. The ethyl acetatesolution was washed with 1.0 N HCl (10 mL), dried over sodium sulfate,then filtered. Solvent was removed by rotary evaporator and the crudeproduct purified by reverse phase preparative HPLC, (C18, 30%–40%CH₃CN/H₂O-0.1% CF₃CO₂H). Fractions containing product were concentratedby rotary evaporator and the resulting aqueous suspension extracted withethyl acetate (3×50 mL). The combined organic layers were dried (sodiumsulfate), filtered, and concentrated to dryness by rotary evaporator.The residue was triturated with ether and dried in vacuo to give thetitle compound as a white solid. ¹H NMR (500 MHz, d₆-Acetone) δ ppm:11.96 (2H, s), 9.25 (2H, s), 8.98 (1H, br s), 7.23 (1H, t, J=7.6 Hz),6.63 (1H, dd, J=8.2, 2.4 Hz), 6.57 (1H, dt, J=8.4, 2.4 Hz), 4.53 (2H, d,J=6.7 Hz), 4.05 (2H, d, J=5.2 Hz), 3.90 (2H, t, J=5.2 Hz), 1.55 (6H, s);HRMS [M+H]⁺ calcd for C₁₇H₁₉N₃O₅F: 364.13088. found: 364.1302.

EXAMPLE 96

Carbamic acid, dimethyl-,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenylester. The title compound can be prepared from intermediate 158,dimethyl-carbamic acid2-{[(3-benzyloxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-pyrimido[2,1-c][1,4]oxazine-2-carbonyl)-amino]-methyl}-5-fluoro-phenylester according to the method described for example 95. Whitecrystalline powder; ¹H NMR (CDCl₃, 500 MHz) δ ppm: 1.56 (6H, s, Me),2.96, 3.11 (2s, NMe), 3.99 (4H, s, CH₂), 4.51 (2H, d, J=6 Hz, NCH₂),6.85 (1H, dd, J=2.5 Hz, 9 Hz, CH), 6.94 (1H, dt, J=2.5 Hz, 8.3 Hz,Ar—H), 7.37 (1H, dd, J=6.5 Hz, 8.5 Hz, Ar—H), 8.05 (1H, brt, J=5 Hz,NH), 12.0 (1H, s, OH); ¹³C NMR (CDCl₃, 125.77 Hz) δ ppm: 27.90 (CH₃),36.68, 36.92 (2s, NCH₃), 37.80 (NCH₂), 43.14 (NCH₂), 58.20 (OCH₂), 75.99(OC), 110.88, 110.07 (d, J=24 Hz, CH), 113.41, 113.57 (d, J=21 Hz, CH),125.71 (C), 125.91, 125.94 (d, J=3.6 Hz, C), 131.57, 131.64 (d, J=9.6Hz, CH), 146.22 (C), 150.83, 150.92 (d, J=11 Hz, C), 151.66 (C), 154.68(C═O), 157.92 (C═O), 161.70, 163.68 (d, J=249 Hz, CF), 167.86 (C═O);HRMS calcd for C₂₀H₂₄N₄O₆F (M+H) 435.1680. found 435.1695 (o+3.5 ppm).UV (MeOH): λmax 245 nm (ε 1.05×10⁴), 306 nm (ε 8.00×10³); Anal. calcdfor C₂₀H₂₃N₄O₆F; C, 55.30; H, 5.34; N, 12.90. found C, 55.32; H, 5.38;N, 12.77.

EXAMPLE 97

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[2-(methylamino)-2-oxoethoxy]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A solution of intermediate 144,N-(4-fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.331 mmol) and sodium hydride (0.015 g, 0.37 mmol, 60% oildispersion) in anhydrous dimethylformamide (4 mL) was stirred for 5minutes under a nitrogen atmosphere. The reaction mixture was treatedwith 2-chloro-N-methylacetamide (0.054 g, 0.50 mmol), and stirred for anadditional 16 hours. Solvent was removed by rotary evaporator, and theresulting residue purified by short path flash silica gel chromatography(ethyl acetate). The fractions containing product were combined andconcentrated to dryness. The residue was dissolved in dichloromethane (5mL) and trifluoroacetic acid (5 mL) and stirred for 1 hour. Solvent wasremoved by rotary evaporator and the crude product was triturated with aminimal volume of 95% ethanol. The resulting solid was collected byfiltration, and dried under vacuum resulting in 93 mg (0.21 mmol, Yield65%) of the title compound as a white powder: ¹H NMR (500 MHz, CDCl₃) δppm: 11.92 (1H, s), 7.67 (1H, t, J=6.3 Hz), 7.57 (1H, br), 7.30 (1H, dd,J=8.2, 6.4 Hz), 6.74 (1H, dt, J=8.2, 2.3 Hz), 6.60 (1H, dd, J=10.4, 2.4Hz), 4.68 (2H, d, J=6.7 Hz), 4.45 (2H, s), 4.00 (4H, s), 2.93 (3H, d,J=4.9 Hz), 1.55 (6H, s). ¹³C NMR (125.77 MHz, CDCl₃) δ ppm: 168.05,167.44, 164.79, 162.82, 157.71, 156.57, 156.50, 152.14, 146.60, 131.94,131.86, 125.23, 120.71, 120.68, 108.37, 108.20, 100.7.6, 100.55, 75.81,67.46, 58.15, 43.24, 38.19, 28.08, 25.83. HRMS [M+H]⁺ calcd forC₂₀H₂₄N₄O₆F: 435.1680. found: 435.1668.

EXAMPLE 98

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[2-(dimethylamino)-2-oxoethoxy-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 144,N-(4-fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamideaccording to the method described for example 97. White powder; ¹H NMR(500 MHz, CDCl₃) δ ppm: 12.25 (1H, br s), 8.36 (1H, t, J=5.65 Hz), 7.31(1H, dd, J=8.39, 6.56 Hz), 6.67 (1H, dt, J=8.32, 2.29 Hz), 6.57 (1H, dd,J=10.38, 2.14 Hz), 4.76 (2H, s), 4.62 (2H, d, J=6.10 Hz), 4.00 (4H, s),3.06 (3H, s), 3.01 (3H, s), 1.58 (6H, s). ¹³C NMR (125.77 MHz, CDCl₃) δppm: 168.25, 166.62, 164.23, 162.27, 158.02, 157.39, 151.36, 146.39,131.25, 131.18, 125.95, 122.23, 122.20, 108.25, 108.08, 100.47, 100.27,76.03, 66.24, 58.22, 43.15, 38.59, 36.07, 35.77, 27.94. HRMS [M+H]⁺calcd for C₂₁H₂₆N₄O₆F: 449.18365. found: 449.1837.

EXAMPLE 99

4-Morpholinecarboxylic acid,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenylester. The title compound can be prepared from intermediate 144,N-(4-fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamideaccording to the method described for example 97. White powder; ¹H NMR(500 MHz, CDCl₃) δ ppm: 12.01 (1H, br s), 7.96 (1H, t, J=5.34 Hz), 7.38(1H, dd, J=8.39, 6.26 Hz), 6.97 (1H, dt, J=8.24, 2.44 Hz), 6.87 (1H, dd,J=8.85, 2.44 Hz), 4.51 (2H, d, J=6.10 Hz), 4.00 (4H, s), 3.70–3.76 (4H,m), 3.65–3.70 (2H, m), 3.49–3.54 (2H, m), 1.55 (6H, s). ¹³C NMR (125.77MHz, CDCl₃) δ ppm: 167.91, 163.68, 157.86, 153.48, 151.71, 150.51,150.42, 146.31, 131.58, 131.50, 125.83, 125.59, 113.84, 113.67, 111.03,110.84, 75.93, 66.59, 66.52, 58.22, 45.17, 44.41, 43.16, 37.70, 27.95.HRMS [M+H]⁺ calcd for C₂₂H₂₆N₄O₇F: 477.17856. found: 477.1788.

EXAMPLE 100

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylthio)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,and (4-fluoro-2-(methylthio)phenyl)methanamine according to the methodsdescribed for the synthesis of examples 1, 19 and 20. White solid. ¹HNMR (300 MHz, CDCl₃) δ ppm: 11.88 (1H, br), 8.03 (1H, t, J=6.04 Hz),7.28 (1H, dd, J=8.42, 5.85 Hz), 6.93 (1H, dd, J=9.51, 2.20 Hz), 6.81(1H, dt, J=8.23, 2.56 Hz), 4.58 (2H, d, J=6.22 Hz), 3.98 (4H, s), 2.49(3H, s), 1.55 (6H, s); HRMS (ESI) calcd for C₁₈H₂₁FN₃O₄S (M+H) 394.1237.found 394.1218.

EXAMPLE 101

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To a solution of example 100 pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylthio)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-(158 mg, 0.4 mmol), in CH₂Cl₂ (4 mL) was added 3-chloroperoxybenzoicacid (132 mg, 0.6 mmol; 77%, Aldrich) and the mixture stirred at roomtemperature for 2 hrs. After removing the solvent in vacuo, the residuewas triturated with diethyl ether. The crude powder was purified byreverse phase column chromatography (YMC, ODS, 8% CH₃CN/H₂O-0.1%CF₃CO₂H) to provide 32 mg (0.075 mmol, Yield 19%) of the title compoundas a white powder after trituration with diethyl ether, and 35 mg (0.086mmol, Yield 21%) of the corresponding sulfoxide. ¹H NMR (300 MHz, CDCl₃)δ ppm: 11.71 (1H, s), 8.58 (1H, t, J=6.04 Hz), 7.73 (1H, dd, J=8.23,2.74 Hz), 7.68 (1H, dd, J=8.42, 5.12 Hz), 7.32 (1H, dt, J=8.05, 2.93Hz), 4.79 (2H, d, J=6.95 Hz), 3.97 (4H, s), 3.15 (3H, s), 1.56 (6H, s);HRMS (ESI) calcd for C₁₈H₁₉FN₃O₆S (M−H) 424.0979. found 424.0973.

EXAMPLE 102

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylsulfinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo.Formed in the reaction described for example 101. ¹H NMR (300 MHz,CDCl₃) δ ppm: 11.73 (1H, s), 8.19 (1H, t, J=6.59 Hz), 7.54 (1H, dd,J=8.05, 2.93 Hz), 7.47 (1H, dd, J=8.42, 5.12 Hz), 7.16 (1H, dt, J=8.14,2.74 Hz), 4.57–4.81 (2H, m), 3.99 (4H, s), 2.80 (3H, s), 1.56 (6H, s);HRMS (ESI) calcd for C₁₈H₂₁FN₃O₅S (M−H) 410.1196. found 410.1194.

EXAMPLE 103

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(S-methylsulfinimidoyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To a solution of example 100, pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylthio)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-,(245 mg, 0.75 mmol) in CH₂Cl₂ (3 mL) was added tert-butyl azido formate(115 mg, 0.8 mmol; prepared following the procedure described in OrganicSynthesis 1979, 50, 9–12) and ferrous chloride (FeCl₂, 50 mg) and theresulting mixture stirred for 18 hrs. The mixture was diluted withdichloromethane, washed with water, dried (MgSO₄), filtered andconcentrated to yield 450 mg of3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-pyrimido[2,1-c][1,4]oxazine-2-carboxylicacid 4-fluoro-2-(N-tert-butoxycarbonyl-S-methyl)sulfiliminyl-benzylamide as a dark gum; LC/MS m/z 509 (M+H).

A solution of this material, (100 mg) in CF₃CO₂H (1 mL), was stirred for20 min then concentrated. The residue was purified by C-18 reverse phaseHPLC (YMC ODS, 5–10% CH₃CN/H₂O-0.1% CF₃CO₂H) to provide 15 mg (0.037mmol, Yield 21%) of the title compound as the correspondingtrifluoroacetic acid salt. ¹H NMR (300 MHz, DMSO-D6) δ ppm: 11.62 (1H,s), 9.57 (1H, t, J=6.0 Hz), 8.11 (1H, dd, J=8.8, 1.8 Hz), 7.62–7.71 (2H,m), 4.58–4.82 (2H, m), 3.97 (2H, t, J=4.8 Hz), 3.82 (2H, t, J=4.8 Hz),3.37 (3H, s), 1.57 (6H, s); HRMS (ESI) calcd for C₁₈H₂₂FN₄O₄S (M+H)409.1346. found 409.1333.

EXAMPLE 104

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[3-[3-(trifluoromethyl)-3-diaziridinyl]phenyl]methyl]-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand (4-(diaziridin-3-yl)phenyl)methanamine (formed in the preparation ofintermediate 66) according to the methods described for the synthesis ofexamples 1, 19 and 20. White solid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.89(1H, s), 7.81 (1H, t, J=6.0 Hz), 7.52–7.59 (2H, m), 7.38–7.44 (2H, m),4.63 (2H, d, J=6.2 Hz), 4.00 (4H, s), 2.78 (1H, d, J=7.3 Hz), 2.21 (1H,d, J=8.1 Hz), 1.51–1.57 (6H, m); HRMS (ESI) calcd for C₁₉H₂₁F₃N₅O₄ (M+H)440.1546. found 440.1537.

EXAMPLE 105

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[3-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenyl]methyl]-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand intermediate 66,(3-(3-(trifluoromethyl)diaziridin-3-yl)phenyl)methanamine, according tothe methods described for the synthesis of examples 1, 19 and 20. Whitesolid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.86 (1H, s), 7.73–7.84 (1H, m),7.35–7.40 (2H, m), 7.11–7.17 (1H, m, J=2.9 Hz), 7.08–7.11 (1H, m), 4.60(2H, d, J=6.2 Hz), 4.00 (4H, s), 1.55 (6H, s); HRMS (ESI) calcd forC₁₉H₁₉F₃N₅O₄ (M+H) 438.1389. found 438.1371.

EXAMPLE 106

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand intermediate 59,(4-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)methanamine hydrochloride,according to the methods described for the synthesis of examples 1, 19and 20. (white solid); ¹H NMR (300 MHz, CDCl₃) δ ppm: 12.01 (1H, s),9.24 (1H, t, J=6.8 Hz), 7.75 (1H, dd, J=9.5, 2.6 Hz), 7.63 (1H, dd,J=8.4, 5.5 Hz), 7.15 (1H, dt, J=8.2, 2.6 Hz), 4.70 (2H, d, J=7.0 Hz),4.45 (3H, s), 3.96 (4H, s), 1.53 (6H, s); HRMS (ESI) calcd forC₁₉H₂₁FN₇O₄ (M+H) 430.1639. found 430.1649.

EXAMPLE 107

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1-methyl-1H-tetrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand intermediate 62,(4-fluoro-2-(1-methyl-2H-tetrazol-5-yl)phenyl)methanamine hydrochloride,according to the methods described for the synthesis of examples 1, 19and 20. Off-white solid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.83 (1H, s),9.17 (1H, t, J=5.8 Hz), 7.75 (1H, dd, J=8.4, 5.7 Hz), 7.30 (1H, t, J=8.2Hz), 7.14 (1H, d, J=7.9 Hz), 4.43 (2H, d, J=6.7 Hz), 4.14–4.16 (3H, m),4.00 (4H, s), 1.67 (6H, s); HRMS (ESI) calcd for C₁₉H₂₁FN₇O₄ (M+H)430.1639. found 430.1619.

EXAMPLES 108–112

Examples 108–112 can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the methods described for thesynthesis of examples 1, 19 and 20.

EXAMPLE 108

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 48,2-(aminomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide. White solid; ¹HNMR (500 MHz, CDCl₃) δ ppm: 11.83 (1H, s), 8.64 (1H, t, J=6.6 Hz), 7.68(1H, dd, J=8.6, 5.5 Hz), 7.50 (1H, dd, J=8.2, 2.8 Hz), 7.26–7.30 (1H,m), 4.80 (2H, d, J=7.0 Hz), 3.99 (4H, s), 2.91 (6H, s), 1.58 (6H, s);HRMS (ESI) calcd for C₁₉H₂₄FN₄O₆S (M+H) 455.1401. found 455.1402.

EXAMPLE 109

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)sulfonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 52,2-(aminomethyl)-5-fluoro-N-methylbenzenesulfonamide hydrochloride.Off-white solid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.69 (1H, s), 8.55 (1H,br), 7.58–7.67 (2H, m), 7.24–7.29 (1H, m), 4.87–4.97 (1H, br), 4.82 (2H,d, J=6.2 Hz), 3.97 (4H, s), 2.71 (3H, d, J=4.4 Hz), 1.56 (6H, s); HRMS(ESI) calcd for C₁₈H₂₂FN₄O₆S (M+H) 441.1244. found 441.1237.

EXAMPLE 110

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(aminosulfonyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 56,2-(aminomethyl)-5-fluorobenzenesulfonamide hydrochloride. Off-whitesolid, ¹H NMR (300 MHz, DMSO-D6) δ ppm: 11.92 (1H, s), 9.33 (1H, t,J=6.4 Hz), 7.66 (1H, dd, J=8.8, 2.2 Hz), 7.41–7.52 (2H, m), 4.89 (2H, d,J=6.2 Hz), 3.98 (2H, t, J=4.9 Hz), 3.83 (2H, t, J=4.9 Hz), 3.37 (2H,br), 1.55 (6H, s); HRMS (ESI) calcd for C₁₇H₂₀FN₄O₆S (M+H) 427.1088.found 427.1082.

EXAMPLE 111

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1-azetidinylsulfonyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(2-(azetidin-1-ylsulfonyl)-4-fluorophenyl)methanamine, which wassynthesized according to the methods used to prepare intermediate 48.White solid, ¹H NMR (500 MHz, CDCl₃) δ ppm 11.86 (1H, s), 8.57 (1H, t,J=6.3 Hz), 7.65–7.72 (2H, m), 7.26–7.31 (1H, m), 4.82 (2H, d, J=6.7 Hz),3.99 (4H, s), 3.96 (4H, t, J=7.8 Hz), 2.23–2.32 (2H, m), 1.58 (6H, s);HRMS (ESI) calcd for C₂₀H₂₄FN₄O₆S (M+H) 467.1401. found 467.1398.

EXAMPLE 112

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylthio)phenyl]methyl]-4-oxo-.Prepared according to the method described for the synthesis of example100. White solid, ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.55 (6H, s), 2.50 (3H,s), 3.98 (4H, s), 4.65 (2H, d, J=6.6 Hz), 7.1–7.4 (3H, m), 8.11 (1H, t,J=5.9 Hz), 11.94 (1H, s); LC/MS m/z 376 (M+H).

EXAMPLE 113

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylsulfinyl)phenyl]methyl]-4-oxo-.To a solution example 112, pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylthio)phenyl]methyl]-4-oxo-,(112 mg, 0.3 mmol) in CH₂Cl₂ (5 mL) was added 3-chloroperoxybenzoic acid(69 mg, 0.3 mmol; 77%, Aldrich) and the mixture stirred for 5 min. Afterremoving the solvent in vacuo, the residue was purified by preparativereverse phase HPLC (YMC, ODS, 8–15% CH₃CN/H₂O-0.1% CF₃CO₂H) to provide58 mg (0.16 mmol, Yield 53%) of the title compound as a white powderafter trituration with diethyl ether. ¹H NMR (300 MHz, CDCl₃) δ ppm:1.56 (6H, s), 2.80 (3H, s), 3.98 (4H, s), 4.60–4.94 (2H, m), 7.38–7.61(3H, m), 7.65–7.89 (1H, m), 8.34 (1H, t, J=6.4 Hz), 11.82 (1H, s). HRMS(ESI) calcd for C₁₈H₂₂N₃O₅S (M+H) 392.1280. found 392.1281.

EXAMPLE 114

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylsulfonyl)phenyl]methyl]-4-oxo-.To a solution of example 112, pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylthio)phenyl]methyl]-4-oxo-(112 mg, 0.3 mmol) in CH₂Cl₂ (5 mL) was added 3-chloroperoxybenzoic acid(140 mg, 0.62 mmol; 77%, Aldrich) and the mixture stirred for 20 hrs.After removing the solvent in vacuo, the residue was purified bypreparative reverse phase HPLC (YMC, ODS, 15% CH₃CN/H₂O-0.1% CF₃CO₂H) toprovide 61 mg (0.15 mmol, Yield 50%) of the title compound as a whitepowder after trituration with diethyl ether. ¹H NMR (300 MHz, CDCl₃) δppm: 1.56 (6H, s), 3.14 (3H,s), 3.96 (4H, s), 4.83 (2H, d, J=7.0 Hz),7.39–7.57 (1H, m), 7.60–7.68 (2H, m), 8.02 (1H, d, J=8.4 Hz), 8.65 (1H,t, J=7.0 Hz), 11.78 (1H, brs). HRMS (ESI) calcd for C₁₈H₂₂N₃O₆S (M+H)408.1229. found 408.1217.

EXAMPLES 115–116

Examples 115–116 can be prepared from the indicated intermediates byhydrogenolysis or trifluoroacetic acid mediated hydrolysis.

EXAMPLE 115

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-thiazolylamino)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-. The title compound can be prepared from intermediate 163,N-(4-fluoro-2-(thiazol-2-ylamino)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 11.97 (1H, brs), 9.72 (1H, brs), 9.39(1H, t, J=6.3 Hz), 8.14 (1H, dd, J=2.5, 12.0 Hz), 7.31–7.28 (2H, m),6.99 (1H, d, J=3.8 Hz), 6.84 (1H, ddd(dt), J=2.5, 8.3 Hz), 4.52 (2H, d,J=6.3 Hz), 3.96–3.94 (2H, m), 3.82–3.79 (2H, m), 1.54 (6H, s) LCMS(⁺ESI, M+H⁺) m/z 446. HRMS (ESI⁺) calculated for C₂₀H₂₁FN₅O₄S [M+H⁺]:446.1298. found: 446.1292.

EXAMPLE 116

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 164,N-(4-fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 11.97 (1H, brs), 9.66 (1H, brs), 9.37(1H, brt, J=6.1 Hz), 7.99 (1H, brd), 7.29 (1H, brt, J=7.1 Hz), 6.88 (1H,ddd(dt), J=2.5, 8.0 Hz), 4.52 (2H, d, J=6.1 Hz), 3.97–3.94 (2H, m),3.82–3.80 (2H, m), 2.55 (3H, s), 1.54 (6H, s); LCMS (⁺ESI, M+H⁺) m/z461. HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄S [M+H⁺]: 461.1407. found:461.1425.

EXAMPLE 117

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-A solution of intermediate 33, ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(0.208 g, 0.65 mmol) in anhydrous dimethylformamide (2 mL) was stirredwith anhydrous potassium carbonate (0.366 g, 2.6 mmol) at 60° C. for 16hours. This was treated with intermediate 69,(4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride,(0.451 g, 2.08 mmol) and triethylamine (0.5 mL, 3.6 mmol) and stirringcontinued at 100° C. for 16 hours. The solvent was removed by rotaryevaporator and the was purified by preparative reverse phase HPLC (C18,10%–35% CH₃CN/H₂O-0.1% trifluoroacetic acid). Fractions containingproduct were pooled and concentrated by rotary evaporator. The resultingaqueous solution was extracted with ethyl acetate (2×50 mL), and thecombined organic fractions dried (sodium sulfate), filtered, andconcentrated to dryness. The resulting residue was triturated with aminimal volume of 95% ethanol, and the solid collected by filtration togive 103 mg (0.24 mmol, Yield 37%) of the title compound as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.96 (1H, br s), 8.83 (1H, t,J=6.6 Hz), 8.46 (1H, s), 8.17 (1H, s), 7.71 (1H, dd, J=8.5, 6.1 Hz),7.21 (1H, dt, J=8.2, 2.6 Hz), 7.11 (1H, dd, J=8.4, 2.6 Hz), 4.55 (2H,br), 4.44 (2H, d, J=6.7 Hz), 3.67 (2H, t, J=6.4 Hz), 1.91–1.97 (2H, pJ=6.10 Hz), 1.63 (6H, s). ¹³C NMR (125.76 MHz, CDCl₃) δ ppm: 167.97,163.19, 161.20, 158.28, 153.35, 152.90, 147.34, 143.94, 136.89, 134.45,134.37, 128.65, 128.62, 125.01, 117.09, 116.93, 112.42, 112.23, 82.46,60.88, 39.13, 38.56, 27.73, 27.36. HRMS [M+H]⁺ calcd for C₂₀H₂₂N₆O₄F:429.16867. found: 429.1687. Anal calcd for C₂₀H₂₁N₆O₄Fe.0.06H₂O: C,55.93; H, 4.96; N, 19.57; F, 4.42. found: C, 55.80; H, 5.14; N, 19.74;F, 4.46.

EXAMPLE 118

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.The title compound can be prepared from intermediate 148,N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamideaccording to the method described for example 46. White powder; ¹H NMR(500 MHz, DMSO-D6) δ ppm: 12.17 (1H, s), 9.23 (1H, t, J=6.4 Hz), 8.56(1H, q, J=4.3 Hz), 7.41 (1H, dd, J=8.6, 5.8 Hz), 7.34 (1H, dd, J=9.2,2.8 Hz), 7.30 (1H, dt, J=8.6, 2.8 Hz), 4.55 (2H, d, J=6.4 Hz), 4.37 (2H,br), 3.64 (2H, t, J=6.4 Hz), 2.80 (3H, d, J=4.6 Hz), 1.80–1.86 (2H, m),1.57 (6H, s); HRMS [M+H]⁺ calcd for C₂₀H₂₃N₄O₅F: 419.17308. found:419.1713.

EXAMPLE 119

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from intermediate 31, ethyl9,9-diethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,and intermediate 69,(4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride,according to the methods described for examples 1, 19 and 20. Whitepowder; ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.89 (1H, br s), 8.81 (1H, t,J=6.6 Hz), 8.46 (1H, s), 8.15 (1H, s), 7.69 (1H, dd, J=8.6, 5.8 Hz),7.22 (1H, dt, J=8.2, 2.6 Hz), 7.12 (1H, dd, J=8.4, 2.6 Hz), 4.45 (2H, d,J=6.7 Hz), 3.95–4.02 (4H, m), 1.95–2.03 (2H, m), 1.87–1.96 (2H, m), 0.86(6H, t, J=7.5 Hz). ¹³C NMR (125.76 MHz, CDCl₃) δ ppm: 167.98, 163.19,161.20, 157.88, 152.81, 151.29, 146.05, 143.97, 137.00, 136.93, 134.28,134.21, 128.62, 128.59, 125.85, 117.10, 116.94, 112.58, 112.38, 80.93,58.63, 43.02, 39.20, 31.43, 7.86. HRMS [M+H]⁺ calcd for C₂₁H₂₄N₆O₄F:443.18432. found: 443.1845.

EXAMPLE 120

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.A solution of intermediate 31, ethyl9,9-diethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.228 g, 0.77 mmol) in anhydrous dimethylformamide (5 mL) was treatedwith anhydrous potassium carbonate (0.279 g, 2.0 mmol) followed bybenzyl bromide (0.145 g, 0.85 mmol), and the mixture stirred for 16hours. The mixture was treated with lithium hydroxide (0.042 g, 1.75mmol) and water (2 mL) and stirred for 20 hours. The reaction mixturewas diluted with water (30 mL) and brought to pH 1 with 6 N hydrochloricacid. The crude product was extracted with ethyl acetate (2×30 mL). Thecombined organic layers were dried (sodium sulfate), filtered, andconcentrated to dryness.

A solution of this material, in anhydrous dimethylformamide (4 mL), wastreated with HATU (0.32 g, 0.83 mmol) and stirred for 10 minutes. Thereaction mixture was treated with intermediate 39,2-aminomethyl-5-fluoro-N-methyl-benzamide trifluoroacetic acid salt,(0.281 g, 0.94 mmol), followed by dimethylaminopyridine, DMAP, (0.140 g,1.125 mmol), and stirred at 60° C. for 3 hours. Solvent was removed byrotary evaporator and the residue purified by flash columnchromatography, eluting with 50% to 60% ethyl acetate in hexanes.Fractions containing the product were pooled and concentrated todryness, which gave a white glassy solid. A sample (approximately 10 mg)was further dried under vacuum, and the remainder used in the followingreaction: ¹H NMR (500 MHz, CDCl₃) δ ppm: 8.47 (1H, t, J=6.2 Hz),7.36–7.45 (3H, m), 7.23–7.27 (2H, m), 7.10 (1H, dd, J=8.8, 2.9 Hz), 7.04(1H, dt, J=8.3, 2.7 Hz), 6.60–6.69 (1H, br), 5.25 (2H, s), 4.50 (2H, d,J=6.2 Hz), 3.94 (4H, s), 2.95 (3H, d, J=5.1 Hz), 1.90–2.02 (5H, m),0.75–0.82 (6H, m).

A solution of the above compound in dichloromethane (5 mL) andtrifluoroacetic acid (5 mL) was stirred for 2 hours. The solvent wasremoved and the crude product was purified by preparative reverse phaseHPLC (C-18 column, 10% to 40% CH₃CN/H₂O-0.1% CF₃CO₂H). Fractionscontaining product were pooled and concentrated in vacuo. The resultingaqueous suspension was extracted with dichloromethane (4×100 mL), andthe combined organic extracts, dried (sodium sulfate), filtered, andconcentrated to dryness. The residue was recrystallized ethanol/H₂O toprovide 0.012 g (0.028 mmol, Yield 4%) of the title compound as a whitesolid. ¹H NMR (500 MHz, DMSO-D6) δ ppm: 12.10 (1H, s), 9.30 (1H, t,J=6.4 Hz), 8.52 (1H, m), 7.39 (1H, dd, J=8.4, 5.7 Hz), 7.26–7.35 (2H,m), 4.57 (2H, d, J=6.4 Hz), 3.94 (2H, t, J=4.9 Hz), 3.84 (2H, t, J=4.9Hz), 2.79 (3H, d, J=4.6 Hz), 1.99–2.09 (2H, m), 1.81–1.91 (2H, m), 0.77(6H, t, J=7.3 Hz). ¹³C NMR (125.76 MHz, DMSO-D6) δ ppm: 167.86, 167.57,159.65, 156.86, 151.21, 145.10, 137.26, 137.21, 132.52, 130.75, 130.68,125.39, 116.69, 116.52, 114.71, 114.53, 80.04, 57.60, 42.62, 40.05,30.04, 26.03, 7.47. HRMS [M+H]⁺ calcd for C₂₁H₂₆N₄O₅F: 433.18873. found:433.1872.

EXAMPLES 121–130

Examples 121–130 can be prepared from the indicated intermediatesaccording to the methods described for examples 121 and 122.Alternatively, the examples can be formed by treating the indicatedintermediates with trifluoroacetic acid.

EXAMPLE 121

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-oxo-1-piperidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To intermediate 145,N-(4-fluoro-2-(2-oxopiperidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazin-4(9H)-one,(100 mg, 0.187 mmol) in ethyl acetate (10 mL) was added palladium (10%on charcoal) (30 mg). The reaction mixture was stirred at 23° C. under ahydrogen atmosphere (balloon) for 3 h. The catalyst was removed byfiltration on Celite. The filtrate was concentrated in vacuo and theresulting residue triturated with diethyl ether (10 ml) and dried invacuo to afford 37 mg (45% yield) of the title compound. IR (KBr, cm⁻¹)3397, 2943, 1636, 1539, 1173. ¹HNMR 400 MHz (MeOD) δ ppm: 7.51 (1H, dd,(t), J=7.0 Hz), 7.11 (2H, m), 4.70 (1H, d, J=15.3 Hz), 4.24 (1H, d,J=15.3 Hz), 4.05 (2H, m), 3.96 (2H, m,), 3.73 (1H, m), 3.62 (1H, m),2.63–2.48 (2H, m), 2.03 (4H, broad s), 1.62 (6H, s). LCMS (M+H)⁺ m/z445.

EXAMPLE 122

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-.To intermediate 161,N-(4-fluoro-2-(2-oxopiperidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazin-4(9H)-one(100 mg, 0.187 mmol) in ethyl acetate (10 mL) was added palladium (10%on charcoal) (30 mg). The reaction mixture was stirred at 23° C. under ahydrogen atmosphere (balloon) for 3 h. The catalyst was removed byfiltration on Celite. The filtrate was concentrated in vacuo and theresulting residue triturated with diethyl ether (10 ml) and dried invacuo to afford 37 mg (45%) of the title compound. IR (KBr, cm⁻¹) 3397,2943, 1636, 1539, 1173. ¹HNMR 400 MHz (MeOD) δ ppm: 7.51 (1H, dd, (t),J=7.0 Hz), 7.11 (2H, m), 4.70 (1H, d, J=15.3 Hz), 4.24 (1H, d, J=15.3Hz), 4.05 (2H, m), 3.96 (2H, m,), 3.73 (1H, m), 3.62 (1H, m), 2.63–2.48(2H, m), 2.03 (4H, broad s), 1.62 (6H, s). LCMS (M+H)⁺ m/z 445.

EXAMPLE 123

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(2-oxo-1-azetidinyl)phenyl]methyl]-.The title compound can be prepared from intermediate 162,N-(2-(2-oxoazetidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, CDCl₃) δ ppm: 12.15 (1H, brs), 9.65 (1H, brs),7.33–7.20 (4H, m), 4.54 (2H, d, J=6.6 Hz), 3.96–3.94 (2H, m), 3.82–3.79(2H, m), 3.76 (2H, t, J=4.3 Hz), 3.10 (2H, t, J=4.3 Hz), 1.53 (6H, s);LCMS (⁺ESI, M+H⁺) m/z 399.

EXAMPLE 124

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-oxo-1-pyrrolidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo.The title compound can be prepared from intermediate 159,N-(4-fluoro-2-(2-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.IR (KBr, cm⁻¹) 3432, 2980, 1689, 1543, 1183. ¹HNMR 400 MHz (MeOD) δ ppm:7.53 (1H, dd, J=9.2, 6.3 Hz), 7.11 (2H, m), 4.52 (2H, s), 4.05 (2H, t,J=5.0 Hz), 3.96 (2H, m), 3.87 (2H, t, J=7.1 Hz), 2.61 (2H, t, J=8.0 Hz),2.26 (2H, m), 1.6 (6H, s). HRMS (ESI⁺) calculated for C₂₁H₂₄FN₄O₅[M+H⁺]: 431.1731. found: 431.1714.

EXAMPLE 125

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(hexahydro-2-oxo-1H-azepin-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 160,N-(4-fluoro-2-(2-oxoazepan-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2carboxamide. IR (KBr, cm⁻¹) 3392, 2934, 1646, 1522, 1292. ¹HNMR 400 MHz(MeOD) δ ppm: 7.50 (1H, broad s), 7.06 (1H, broad s), 7.01 (1H, d, J=9.0Hz), 4.64 (1H, d, J_(AB)=15.0 Hz), 4.31 (1H, d, J_(AB)=15 Hz), 4.04 (2H,m), 3.96 (3H, m), 3.66 (1H, m), 2.86 (1H, m), 2.65 (1H, m), 2.03–1.80(6H, m), 1.62 (6H, s), (2H, m). LCMS (M+H)⁺ m/z 459.

EXAMPLE 126

N-(4-Fluoro-2-(2-oxoazetidin-1-yl)benzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 146,N-(4-fluoro-2-(2-oxoazetidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ: 9.46 (d, J=6.4 Hz), 7.34 (1H, dd, J=8.5,6.4 Hz), 7.25 (1H, dd, J=10.2, 2.6 Hz), 7.08 (1H, td, J=8.5, 2.6 Hz),6.90 (1H, m), 4.52 (2H, d, J=6.4 Hz), 3.96 (2H, t, J=5.0 Hz), 3.83–3.77(4H, m), 3.11 (2H, t, J=5.0 Hz), 1.53 (6H, s); LCMS (M+H)⁺ m/z 417.

EXAMPLE 127

N-(4-Fluoro-2-(2-oxooxazolidin-3-yl)benzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 165,N-(4-fluoro-2-(2-oxooxazolidin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.12 (1H, s), 9.34 (1H, t, J=6.2 Hz),7.41 (1H, m), 7.23 (1H, td, J=8.6, 2.5 Hz), 4.48 (4H, m), 4.06 (2H, t,J=7.7 Hz), 3.97 (2H, t, J=5.0 Hz), 3.83 (2H, t, J=5.0 Hz), 1.55 (6H, s).LCMS (M+H)⁺ m/z 433.

EXAMPLE 128

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(2R)-2-(hydroxymethyl)-5-oxo-1-pyrrolidinyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 192,(R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.IR (KBr, cm⁻¹) 3441, 2979, 1684, 1540, 1172. ¹HNMR 400 MHz (MeOD) δ ppm:7.56 (1H, m), 7.15 (2H, m), 4.86–4.31 (3H, m), 4.06 (2H, t, 5.0 Hz),3.98 (2H, t, 5.0 Hz), 3.57 (2H, broad s), 2.72–2.55 (2H, m), 2.41 (1H,m), 2.25 (1H, m), 1.62 (6H, s). LCMS (M+H)⁺ m/z 461.

EXAMPLE 129

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(2R)-2-[(acetyloxy)methyl]-5-oxo-1-pyrrolidinyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 193,(R)-(1-(2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-ylmethylacetate. ¹HNMR 400 MHz (MeOD) δ ppm: 7.58 (1H, m), 7.21–7.04 (2H, m),5.24 (2H, s), 4.66–4.21 (3H, m), 4.02–3.92 (5H, m), 2.73–2.34 (3H, m),2.23–1.61 (5H, m), 1.60 (6H, s). LCMS (M+H)⁺ m/z 503.

EXAMPLE 130

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(2S)-2-(hydroxymethyl)-5-oxo-1-pyrrolidinyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 167,(S)-N-(2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (DMSO) δ ppm: 7.36 (1H, m), 7.18 (2H, m), 5.07 (1H, broads), 4.66–4.11 (3H, m), 3.95 (2H, t, 5.1 Hz), 3.80 (2H, t, 5.1 Hz), 3.39(2H, s), 2.43 (1H, m), 2.25 (1H, m), 2.08 (1H, m), 1.51 (6H, s). LCMS(M+H)⁺ m/z 461.

EXAMPLE 131

(R)-N-(2-(2-((Dimethylamino)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 195,(R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.050 g, 0.087 mmol) in MeOH (5 mL) was added Palladium (10%) oncharcoal (0.020 g) and formaldehyde (0.30 mL, 10 mmol). The reactionmixture was stirred at 23° C. under H₂ (balloon) for 5 h. Palladium oncharcoal was then removed by filtration and the solvent was evaporatedin vacuo. The residue was purified by preparative HPLC (YMC-Pack C-18)to afford the title compound (0.013 g, 29% yield): ¹H NMR (400 MHz,MeOD) δ ppm: 7.56 (1H, dd, J=7.0 Hz), 7.30–7.17 (2H, m), 4.70 (2H, m),4.15 (1H, d, J=15.3 Hz), 4.07 (2H, m), 3.99 (2H, m,), 3.54 (1H, m), 2.93(6H, s), 2.84–2.64 (4H, m), 2.20 (1H, m), 1.65 (6H, s). HRMS calcd forC₂₄H₃₁N₅O₅F: 488.2309. found 488.2328.

EXAMPLE 132

(R)-N-(2-(2-(Azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 195,(R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0 030 g, 0.052 mmol) in CH₂Cl₂ (1 mL) was added CF₃CO₂H (1 mL) at 23°C. The reaction mixture was stirred at 23° C. for 3 h. Toluene (20 mL)was then added and the solvents evaporated in vacuo. The residue waspurified by preparative HPLC (YMC-Pack C-18) to afford the titlecompound (0.008 g, 31%): ¹H NMR (400 MHz, MeOD) δ ppm: 7.55 (1H, dd,J=6.6 Hz), 7.16 (2H, m), 4.47–4.24 (2H, m), 4.05 (2H, m), 3.98 (2H, m),3.56 (2H, s), 2.70–2.45 (4H, m), 2.11 (1H, m), 1.64 (3H, s), 1.61 (3H,s). HRMS calcd for C₂₂H₂₅N₇O₅F: 486.1901. found 486.1923.

EXAMPLE 133

(R)-N-(2-(2-(Aminomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared by hydrogenolysis (H₂, 110% Pd—C) ofintermediate 195,(R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, MeOD) δ ppm: 7.54 (1H, dd, J=7.0 Hz), 7.25–7.13 (2H,m), 4.62 (2H, m), 4.17 (1H, d, J=15.6 Hz), 4.07 (2H, m), 3.99 (2H, m,),3.23 (2H, d, J=3.1 Hz), 2.79–2.59 (3H, m), 2.14 (1H, m), 1.66 (6H, s).HRMS calcd for C₂₂H₂₇N₅O₅F: 460.1996. found 460.2014.

EXAMPLES 134–136

Examples 134–136 can be prepared from the indicated intermediates byhydrogenolysis or trifluoroacetic acid mediated hydrolysis.

EXAMPLE 134

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-amino-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 169,N-(2-amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.IR (KBr, cm⁻¹) 3383, 2979, 1636, 1540, 1288. ¹HNMR 400 MHz (MeOD) δ ppm:7.14 (1H, dd, J=7.3 Hz), 6.44–6-31 (2H, m), 4.69 (1H, broad s), 4.48(2H, broad s), 4.03 (2H, t, J=4.6 Hz), 3.95 (2H, t, J=4.6 Hz), 1.62 (6H,s). HRMS (ESI⁺) calculated for C₁₇H₂₀FN₄O₄ [M+H⁺]: 363.1469. found:363.1454.

EXAMPLE 135

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(acetylamino)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 189,N-(2-acetamido-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (MeOD) δ ppm: 7.66 (1H, broad d, J=10.5 Hz), 7.40 (1H,broad t, 6.5 Hz), 6.87 (1H, broad t, J=6.5 Hz), 4.55 (2H, m), 4.02 (2H,t, J=5.0 Hz), 3.92 (2H, t, J=5.0 Hz), 2.28 (3H, s), 1.62 (6H, s). HRMS(ESI⁺) calculated for C₁₉H₂₂FN₄O₅ [M+H⁺]: 405.1574. found: 405.1571.

EXAMPLE 136

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(acetylmethylamino)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 168,N-(4-fluoro-2-(N-methylacetamido)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.IR (KBr, cm⁻¹) 3407, 2979, 1653, 1539, 1116. ¹HNMR 400 MHz (MeOD) δ ppm:7.53 (1H, m), 7.24–7.06 (2H, m), 4.61–4.45 (2H, m), 4.08 (2H, t, J=5.1Hz), 4.00 (2H, t, J=5.1 Hz), 3.40 (0.6H, s), 3.25 (2.4H, s), 1.85 (2.4H,s), 1.81 (0.6H, s), 1.65 (2.4H, s), 1.64 (2.4H, s), 1.62 (1.2H, s). LCMS(M+H)⁺ m/z 419.

EXAMPLE 137

N-(2-(2,5-Dioxo-2H-pyrrol-1(5H)-yl)benzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution ofN-(2-aminobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0 050 g, 0.114 mmol) in acetic acid (1.5 mL) was added maleic anhydride(0.013 g, 0.131 mmol) and the reaction mixture stirred in a sealed tubeat 115 C for 18 h. Acetic acid was evaporated in vacuo and the residuewas purified by preparative HPLC (YMC-Pack C-18) to afford the titlecompound (0.013 g, 27% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.03 (1H,broad t), 7.59 (1H, m), 7.48 (2H, m), 7.19 (1H, m), 6.92 (2H, s), 4.48(2H, d, J=6.1 Hz), 4.04 (4H, s), 1.62 (6H, s); HRMS calcd forC₂₁H₂₁N₄O₆: 425.1461. found 425.1451.

EXAMPLE 138

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-(benzo[b]thien-7-ylmethyl)-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To intermediate 147,N-(benzo[b]thiophen-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(60 mg, 0.13 mmol) was added CF₃CO₂H (2 mL) at 23° C. The reactionmixture was stirred at 23° C. for 1.5 h. Toluene (20 mL) was then addedand the solvents were evaporated in vacuo. The residue was purified bypreparative HPLC (YMC-Pack C-18) to afford the title compound (0.017 g,34% yield): ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (1H, broad t), 7.86 (1H, d,J=8.0 Hz), 7.51–7.28 (3H, m), 4.93 (2H, d, J=3.9 Hz), 4.05 (4H, s), 1.58(6H, s). HRMS calcd for C₁₉H₂₀N₃O₄S: 386.1175. found 386.1165.

EXAMPLE 139

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(1,1-dioxidobenzo[b]thien-7-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To intermediate 196,N-(benzo[b]thiophen-1,1-dione-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-.tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.080 g, 0.16 mmol) was added CF₃CO₂H (2 mL) at 23° C. The reactionmixture was stirred at 23° C. for 2.5 h. Toluene (20 mL) was then addedand the solvents evaporated in vacuo. The residue was purified bycrystallization with MeOH (10 mL) to afford the title compound (0.037 g,55% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 11.87 (1H, s), 9.44 (1H, t,J=6.5 Hz), 7.65 (2H, m), 7.51 (1H, d, J=7.0 Hz), 7.42–7.37 (2H, m), 4.84(2H, d, J=6.2 Hz), 3.99 (2H, t, 5.4 Hz), 3.85 (2H, t, J=5.4 Hz), 1.59(6H, s). HRMS calcd for C₁₉H₂₀N₃O₆S: 418.1073. found 418.1078.

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,3-dihydro-]1,1-dioxidobenzo[b]thien-7-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-. The title compound was obtained from intermediate 196,N-(benzo[b]thiophen-1,1-dione-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamideby reduction, Palladium (10%) on charcoal under H₂. ¹HNMR (400 MHz,CDCl₃) δ: 8.65 (1H, s), 7.58–7.49 (2H, m), 7.32 (1H, d, J=7.0 Hz), 4.86(2H, d, J=6.8 Hz), 3.99 (4H, s), 3.54 (2H, t, J=6.8 Hz), 3.40 (2H, t,J=6.8), 1.61 (6H, s). LCMS (M+H)⁺ m/z 420.

EXAMPLES 141–146

Examples 141–146, listed in Table 9, can be prepared from intermediate25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,according to the methods described for examples 1, 19, and 20. Thecompounds in the table were characterized by LCMS; (Xterra MS-C18,4.6×50 mm); eluted with 10% to 100% B, 4.5 min gradient, (A=H₂O-0.1%CF₃CO₂H, B=CH₃CN-0.1% CF₃CO₂H); flow rate at 2.5 mL/min. UV detection at220 nm). Product retention time (RT, minutes) and molecular weight (MS[M+1]) results are listed in the table.

TABLE 9 Example Structure RT MS 141

1.1 331.17 Pyrimido[2,1-c] [1,4]oxazine-2-carbox- amide,4,6,7,9-tetrahydro-3-hydroxy-9,9- dimethyl-4-oxo-N-(2-pyridinylmethyl)-142

2.07 346.18 Pyrimido[2,1-c] [1,4]oxazine-2-carbox- amide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[(5-methylpyrazinyl)methyl]- 4-oxo- 143

3.35 376.16 Pyrimido[2,1-c] [1,4]oxazine-2-carbox- amide,4,6,7,9-tetrahydro-3-hydroxy-9,9-di-methyl-N-[[4-(methylthio)phenyl]methyl]- 4-oxo- 144

2.37 397 Pyrimido[2,1-c] [1,4]oxazine-2-carbox- amide,N-[(2,3-dimethyl-1H-indol-5-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9- dimethyl-4-oxo- 145

2.54 388.2 Pyrimido[2,1-c] [1,4]oxazine-2-carbox- amide,4,6,7,9-tetrahydro-3-hydroxy-9,9- dimethyl-N-[[4-(1-methylethoxy)phenyl]methyl]-4-oxo- 146

3.23 366.15 Pyrimido[2,1-c] [1,4]oxazine-2-carbox- amide,N-[(3,5-difluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl- 4-oxo-

EXAMPLE 147

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-bromophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,and 2-bromobenzylamine according to the methods described for examples1, 19 and 20. ¹H NMR (300 MHz, DMSO-D6) δ ppm: 1.58 (s, 1), 3.84 (t, 2),3.98 (t, 2), 4.54 (d, 2), 7.25 (m, 2), 7.38 (m, 2), 7.64 (d, 1), 9.43(brm, 1), 12.01 (s, 1).

EXAMPLES 148–200

Examples 148–200, listed in table 10, were synthesized according to thefollowing procedure. To a microwave reaction vessel containing a stirbar, was added Pd(Ph₃P)₄ (30 mg, 25 μmol), followed by anhydrous dioxane(0.5 mL). To this was added example 147,pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-bromophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-,(50 mmol), boronic acid or boronate ester reagent (200 μmol), anhydrousdioxane (0.5 mL) and 2M K₃PO₄ aqueous solution (0.25 mL). The reactionvessel was flushed with nitrogen, capped and heated at 120° C. for 10minutes in a microwave reactor. The reaction mixture was filteredthrough a Whatman 0.45 μm syringe filter and the crude product purifiedusing preparative HPLC (Xterra MS-C18, 30×50 mm); Eluted with 30% to100% B, 8 min gradient, (A=10 mM NH₄OAC (aq.), B=CH₃CN); flow rate at 30mL/min. UV detection at 220 nm) to give the title compound.

The compounds in the table were characterized by LCMS; (Xterra MS-C18,4.6×50 mm); eluted with 10% to 100% B, 4.5 min gradient, (A=H₂O-0.1%CF₃CO₂H, B=CH₃CN-0.1% CF₃CO₂H); flow rate at 2.5 mL/min. UV detection at220 nm). Product retention time (RT, minutes) and observed molecularweight (MS [M+1]) results are listed in the table.

TABLE 10 Example Structure RT MS 148

2.08 457 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(8-quinolinyl)phenyl]methyl]- 149

1.91 467.95 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(2,4-dimethoxy-5- pyrimidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 150

1.71 407 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(3-pyridinyl)phenyl]methyl]- 151

1.98 425.01 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(3-pyridinyl)phenyl]methyl]- 152

2.04 437.04 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[[2-(2-methoxy-3-pyridinyl)phenyl]methyl]-9,9- dimethyl-4-oxo- 153

2.1 436.97 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[[2-(5-methoxy-3-pyridinyl)phenyl]methyl]-9,9- dimethyl-4-oxo- 154

2.41 467.01 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(2,6-dimethoxy-3- pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 155

2.19 486.03 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-[1-(phenylmethyl)-1H-pyrazol-4- yl]phenyl]methyl] 156

2 492.01 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N- [[2-[6-(4-morpholinyl)-3-pyridinyl]phenyl]methyl]-4-oxo- 157

3.02 454.97 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(6-amino-3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4- oxo- 158

1.99 438.04 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(1-propyl-1H-pyrazol-4- yl)phenyl]methyl]- 159

1.66 505.05 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-[2-(4-methyl-1-piperazinyl)-4- pyridinyl]phenyl]methyl]-4-oxo- 160

3.2 406 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-([1,1′-biphenyl]-2-ylmethyl)-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 161

3.36 469.91 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4′-chloro-2′-methoxy[1,1′-biphenyl]-2-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9- dimethyl-4-oxo- 162

3.39 419.97 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[(4′-methyl[1,1′-biphenyl]-2-yl)methyl]-4-oxo- 163

3.36 419.97 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[(3′-methyl[1,1′-biphenyl]-2-yl)methyl]-4-oxo- 164

3.14 435.97 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[(3′-methoxy[1,1′-biphenyl]-2-yl)methyl]-9,9- dimethyl-4-oxo- 165

2.65 421.99 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[(3′-hydroxy[1,1′-biphenyl]-2-yl)methyl]-9,9- dimethyl-4-oxo- 166

2.91 430.99 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4′-cyano[1,1′-biphenyl]-2-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4- oxo- 167

2.93 430.99 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3′-cyano[1,1′-biphenyl]-2-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4- oxo- 168

3.02 491 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[4′-(4-morpholinyl)[1,1′-biphenyl]-2- yl]methyl]-4-oxo- 169

2.11 435.02 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[4′-(4-morpholinyl)[1,1′-biphenyl]-2- yl]methyl]-4-oxo- 170

2.54 476.96 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4′-[(dimethylamino)carbonyl][1,1′-biphenyl]-2-yl]methyl]-4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-4-oxo-171

2.53 476.96 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[3′-[(dimethylamino)carbonyl][1,1′-biphenyl]-2-yl]methyl]-4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-4-oxo-172

2.66 502.97 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[3′-(1-pyrrolidinylcarbonyl)[1,1′- biphenyl]-2-yl]methyl]- 173

2.26 448.94 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4′-(aminocarbonyl)[1,1′-biphenyl]-2-yl]methyl-4,6,7,9-tetrahydro-3-hydroxy-9,9- dimethyl-4-oxo- 174

2.27 448.94 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[3′-(aminocarbonyl)[1,1′-biphenyl]-2-yl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9- dimethyl-4-oxo- 175

2.36 462.98 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[4′-[(methylamino)carbonyl][1,1′-biphenyl] 2-yl]methyl]-4-oxo- 176

2.63 498.94 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[3′-[(methylsulfonyl)amino][1,1′-biphenyl]-2- yl]methyl]-4-oxo- 177

3 444.97 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[[2-(1H-indol-5-yl)phenyl]methyl]-9,9-dimethyl-4-oxo- 178

2.56 462.98 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4′-[(dimethylamino)methyl][1,1′-biphenyl]-2-yl]methyl]-4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-4-oxo-179

3.09 411.98 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(3-thienyl)phenyl]methyl]- 180

2.66 425.01 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(3,5-dimethyl-4- isoxazolyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 181

3.08 450.01 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[[4′-(methoxymethyl)[1,1′-biphenyl-2-yl]methyl]- 9,9-dimethyl-4-oxo- 182

2.43 438 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[[2-(2-methoxy-5-pyrimidinyl)phenylmethyl]-9,9- dimethyl-4-oxo- 183

1.71 410 Pyrimido[2,1-c[1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N- [[2-(1-methyl-1H-pyrazol-4-yl)phenyl]methyl]-4-oxo- 184

3.02 455 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(5-fluoro-6-methoxy-3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 185

3.14 436 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[(4′-methoxy[1,1′-biphenyl]-2-yl)methyl]-9,9- dimethyl-4-oxo- 186

3.30 478 [1,1′-Biphenyl]-4-carboxylic acid, 2′-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2- yl)carbonyl]amino]methyl]-, ethylester 187

2.76 450.2 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1,3-benzodioxol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4- oxo- 188

2.92 442.13 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide, N-[(3′,4′-difluoro[1,1′-biphenyl]-2-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4- oxo 189

2.57 445.15 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4′-(cyanomethyl)[1,1′-biphenyl]-2-yl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9- dimethyl-4-oxo- 190

1.34 407.34 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(4-pyridinyl)phenyl]methyl]- 191

1.40 421.2 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(4-methyl-3-pyridinyl)phenyl]methyl]-4- oxo- 192

2.57 439.36 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(6-fluoro-5-methyl-3-pyridinyl)phenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 193

2.84 471.13 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(5-chloro-6-methoxy-3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 194

1.62 457.26 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(3-quinolinyl)phenyl]methyl]- 195

1.57 520.31 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide, N-[[3′-[[[2-(dimethylamino)ethyl]amino]carbonyl][1,1′-biphenyl]-2-yl]methyl]-4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-4-oxo-196

1.57 532.41 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[4′-[(4-methyl-1-piperazinyl)carbonyl][1,1′-biphenyl]-2-yl]methyl]-4-oxo- 197

1.55 457.26 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(5-quinolinyl)phenyl]methyl]- 198

2.86 396.2 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(3-furanyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 199

3.08 451.2 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(6-ethoxy-3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4- oxo 200

3.33 396.34 Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1-cyclopenten-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4- oxo-

EXAMPLE 201

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2,5-dibromophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo.A mixture of (2,5-dibromo-4-fluorophenyl)methanamine (1 mmol),intermediate 25 (0.268 g, 1 mmol) and triethylamine (0.5 mL, 3.5 mmol)in ethanol/dimethylformamide (1:1, 3 mL) was heated at 100° C. for 6 h.After cooling, the reaction mixture was purified by preparative HPLC toafford the title compound (0.31 g, 62% yield) as an off-white solid. ¹HNMR (500 MHz, CDCl₃) δ ppm: 11.72 (1H, s), 8.08 (1H, t, J=6.1 Hz), 7.61(1H, d, J=7.0 Hz), 7.38 (1H, d, J=7.6 Hz), 4.61 (2H, d, J=6.4 Hz), 4.02(4H, s), 1.59 (6H, s).

EXAMPLE 202

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.Off-white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.77 (1H, br s), 8.55(1H, t, J=6.3 Hz), 7.75 (1H, dd, J=8.1, 2.6 Hz), 7.72 (1H, dd, J=8.5,5.2 Hz), 7.34 (1H, td, J=8.0, 2.6 Hz), 4.81 (2H, d, J=6.7 Hz), 4.54 (2H,br), 3.65 (2H, t, J=6.1 Hz), 3.18 (3H, s), 1.93 (2H, m), 1.59 (6H, s);¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.14, 163.14, 161.13, 158.23, 153.73,147.26, 140.77, 140.72, 135.31, 135.25, 132.83, 132.80, 124.83, 121.69121.52, 117.63, 117.43, 82.56, 60.80, 45.14, 40.24, 38.62, 27.76, 27.35.HRMS (ESI) calcd for C₁₉H₂₃N₃O₆FS (M+H): 440.1292. found: 440.1300.Anal. Calcd for C₁₉H₂₂N₃O₆FS.0.06H₂O: C, 51.80; H, 5.06; N, 9.54; F,4.31. found C, 51.83; H, 4.97; N, 9.29; F, 4.12.

EXAMPLE 203

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm: 11.74 (1H, s), 8.54 (1H, t, J=6.6 Hz),7.75 (1H, dd, J=8.2, 2.7 Hz), 7.71 (1H, dd, J=8.5, 5.2 Hz), 7.34 (1H,td, J=8.0, 2.6 Hz), 4.82 (2H, d, J=7.0 Hz), 3.94–4.00 (4H, m), 3.17 (3H,s), 1.93–2.00 (2H, m), 1.84–1.92 (2H, m), 0.83 (6H, t, J=7.3 Hz); ¹³CNMR (126 MHz, CDCl₃) δ ppm: 168.26, 163.13, 161.11, 157.83, 151.66,146.05, 140.69, 140.64, 135.13, 135.07, 132.80, 132.77, 125.63, 121.65,121.48, 117.65, 117.45, 81.03, 58.51, 45.14, 43.08, 40.33, 31.38, 7.87.HRMS (ESI) calcd for C₂₀H₂₅N₃O₆FS (M+H): 454.1448. found: 454.1448.Anal. calcd for C₂₀H₂₄N₃O₆FS: C, 52.97; H, 5.33; N, 9.27; S, 7.07.found: C, 53.01; H, 5.60; N, 9.10; S, 7.00.

EXAMPLE 204

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.Pale orange solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.87 (1H, br s), 8.59(1H, t, J=6.4 Hz), 7.69 (1H, dd, J=8.5, 5.2 Hz), 7.49 (1H, dd, J=8.2,2.4 Hz), 7.26 (1H, td, J=7.7, 3.2 Hz), 4.79 (2H, d, J=6.7 Hz), 4.53 (2H,br), 3.65 (2H, t, J=6.1 Hz), 2.90 (6H, s), 1.89–1.96 (2H, m), 1.57–1.61(6H, s); ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.03, 162.71, 160.70, 158.29,153.57, 147.23, 138.51, 138.46, 135.30, 135.25, 132.70, 132.67, 124.99,120.40, 120.24, 116.93, 116.73, 82.59, 60.79, 58.57, 40.26, 38.58,37.59, 27.74, 27.36, 18.55. HRMS (ESI) calcd for C₂₀H₂₆N₄O₆FS (M+H)469.1557. found 469.1557. Anal. calcd for C₂₀H₂₆N₄O₆FS.CH₃CH₂OH: C,51.29; H, 6.07; N, 10.89; S, 6.01; F, 3.69. found C, 51.29; H, 6.33; N,10.85; S, 6.01; F, 3.54.

EXAMPLE 205

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-9,9-diethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.White glassy solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.85 (1H, br), 8.59(1H, t, J=6.4 Hz), 7.68 (1H, dd, J=8.5, 5.2 Hz), 7.49 (1H, dd, J=8.2,2.4 Hz), 7.24–7.30 (1H, m), 4.80 (2H, d, J=7.0 Hz), 3.94–4.01 (4H, m),2.90 (6H, s), 1.93–2.01 (2H, m), 1.85–1.93 (2H, m), 0.83 (6H, t, J=7.3Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.04, 162.70, 160.70, 158.06,151.44, 145.95, 138.53, 138.49, 135.17, 135.12, 132.62, 132.59, 125.95,120.37, 120.21, 116.87, 116.68, 81.08, 58.51, 43.11, 40.32, 37.58,31.35, 7.87. HRMS (ESI) calcd for C₂₁H₂₈N₄O₆FS (M+H) 483.1714. found483.1702. Anal. calcd for C₂₁H₂₇N₄O₆FS.0.15 CF₃CO₂H: C, 51.20; H, 5.48;N, 11.21; F, 5.51; S, 6.42. found: C, 51.10; H, 5.23; N, 11.21; F, 5.49;S, 6.32.

EXAMPLE 206

6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-.Off-white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 12.18 (1H, br s),8.14–8.25 (1H, br), 7.41–7.50 (2H, m), 7.31–7.39 (2H, m), 4.96 (1H, dd,J=14.0, 8.9 Hz), 4.54 (2H, br s), 4.44 (1H, dd, J=14.2, 3.2 Hz),3.83–3.92 (1H, m), 3.65 (2H, br), 3.38–3.46 (1H, m), 3.18–3.28 (2H, m),2.32–2.42 (2H, m), 1.89–1.98 (4H, m), 1.55 (6H, d, J=15.9 Hz); ¹³C NMR(126 MHz, CDCl₃) δ ppm: 168.22, 158.38, 153.54, 147.32, 138.80, 137.00,130.88, 129.47, 129.29, 127.68, 125.17, 82.60, 60.74, 54.15, 51.05,39.11, 38.63, 27.76, 27.73, 27.36, 25.04, 24.32. HRMS (ESI) calcd forC₂₂H₂₉N₄O₆S (M+H): 477.1808. found: 477.1794. Anal. calcd forC₂₂H₂₈N₄O₆S.0.5CH₃CH₂OH: C, 55.45; H, 5.92; N, 11.76; S, 6.73. found: C,55.36; H, 6.11; N, 11.46; S, 6.48.

EXAMPLE 207

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-diethyl-4-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl].Off-white crystalline solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 12.11 (1H,br s), 8.20 (1H, br), 7.42–7.48 (2H, m), 7.33–7.40 (2H, m), 4.93 (1H,dd, J=14.2, 8.4 Hz), 4.45 (1H, dd, J=14.2, 3.8 Hz), 3.94–4.02 (4H, m),3.87 (1H, ddd, J=13.0, 9.9, 3.7 Hz), 3.39–3.46 (1H, m), 3.15–3.24 (2H,m), 2.29–2.46 (2H, m), 1.79–2.04 (6H, m), 0.81 (3H, t, J=6.7 Hz), 0.78(3H, t, J=7.3 Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.25, 157.91,151.43, 146.14, 139.14, 136.81, 130.79, 129.46, 129.25, 127.90, 125.96,81.15, 58.55, 54.22, 51.09, 43.03, 39.57, 31.21, 25.03, 24.34, 7.82,7.68. HRMS (ESI) calcd for C₂₃H₃₁N₄O₆S (M+H): 491.1964. found: 491.1953.Anal. calcd for C₂₃H₃₀N₄O₆S: C, 56.12; H, 6.48; N, 10.91; S, 6.24.found: C, 56.14; H, 6.44; N, 11.07; S, 6.05.

EXAMPLE 208

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-[2-(methylthio)ethyl]-4-oxo-.A solution of intermediate 141,N-(4-fluorobenzyl)-3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamidein 4 mL CF₃CO₂H was stirred at 60° C. for 1 hr then concentrated. Theresidue was dissolved in CH₂Cl₂ and washed with water then concentrated.Trituration with hexanes gave the title compound as a solid. ¹H NMR (300MHz, CDCl₃) δ ppm: 12.03 (1H, s) 7.75 (1H, m) 6.84–7.40 (4H, m)4.39–4.72 (3H, m) 4.04–4.36 (2H, m) 3.68–3.92 (2H, m) 2.49–2.73 (2H, m)2.07–2.50 (2H, m) 2.02 (3H, s); HRMS (ESI) calcd for C₁₈H₂₀FN₃O₄S (M+H):394.1237. found: 394.1234.

EXAMPLE 209

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-[2-(methylsulfonyl)ethyl]-4-oxo-.A solution of example 208, pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-[2-(methylthio)ethyl]-4-oxo-,(40 mg, 0.1 mmol) in 2 mL CH₂Cl₂ was treated with excessm-chloroperbenzoic acid (100 mg, 0.4 mmol) and stirred at roomtemperature for 20 hrs. The reaction mixture was washed with water andconcentrated. The crude material was purified by reverse phase HPLC(C18, 12% CH₃CN/H₂O). The fractions containing the product wereconcentrated and lyophilized to afford 5 mg (12% yield) of the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm: 12.10–12.27 (1H, s) 7.80–8.02(1H, m) 7.25–7.39 (2H, m) 6.90–7.09 (2H, m) 4.05–4.72 (5H, m) 3.73–3.99(2H, m) 3.02–3.34 (2H, m) 2.86–2.91 (3H, s) 2.35–2.78 (2H, m); HRMS(ESI) calcd for C₁₈H₂₀FN₃O₆S (M+H): 426.1135. found: 426.1143.

EXAMPLE 210

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-methyl-5-isoxazolyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 180,N-(4-fluoro-2-(3-methylisoxazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.59 (6H, s, 2×CH₃), 2.42 (3H, s, CH₃),4.03 (4H, s, 2×CH₂), 4.74 (2H, d, J=6.6 Hz, NCH₂), 6.40 (1H, s,aromatic), 7.18 (1H, m, aromatic), 7.32 (1H, dd, J=2.5 Hz and J=9.1 Hz,aromatic), 7.59 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.29 (1H,broad t, NH), 11.87 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₂FN₄O₅[M+H⁺]: 429.1574. found: 429.1584.

EXAMPLE 211

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(2Z)-3-amino-1-oxo-2-butenyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 2.11 (3H, s, CH₃),4.03 (4H, s, 2×CH₂), 4.58 (2H, d, J=6.5 Hz, NCH₂), 5.38 (1H, broad, NH),5.49 (1H, s, CH), 7.09 (1H, m, aromatic), 7.29 (1H, dd, J=3.0 Hz andJ=9.1 Hz, aromatic), 7.48 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic),9.19 (1H, broad t, NH), 10.26 (1H, broad, NH), 12.21 (1H, s, OH).

EXAMPLE 212

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(3-bromo-5-isoxazolyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 181,N-(2-(3-bromoisoxazol-5-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.60 (6H, s, 2×CH₃), 4.03 (4H, s, 2×CH₂),4.74 (2H, d, J=7.1 Hz, NCH₂), 6.63 (1H, s, aromatic), 7.24 (1H, m,aromatic), 7.32 (1H, dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.63 (1H, dd,J=5.5 Hz and J=8.6 Hz, aromatic), 8.20 (1H, broad t, NH), 11.77 (1H, s,OH).

EXAMPLE 213

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,diethyl ester. Hydrogenolysis of intermediate 187, diethyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate(0.089 g, 0.15 mmol) gave 0.065 g (90% yield) of the title compound as awhite solid: mp 124° C. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.39 (6H, t, J=7.1Hz, 2×CH₃), 1.63 (6H, s, 2×CH₃), 4.02 (4H, s, 2×CH₂), 4.20 (4H, m,2×OCH₂), 4.78 (2H, d, J=6.6 Hz, NCH₂), 7.25 (1H, m, aromatic), 7.49 (1H,m, aromatic), 7.63 (1H, m, aromatic), 9.12 (1H, broad t, NH)., 12.1 (1H,broad, OH). HRMS (ESI⁺) calculated for C₂₁H₂₈FN₃O₇P [M+H⁺]: 484.1649.found: 484.1646.

EXAMPLE 214

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-N-methoxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 171,N-(4-fluorobenzyl)-3-(benzyloxy)-N-methoxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (DMSO-d₆) δ ppm: (mixture of rotamers) 1.52 (6H, s,2×CH₃), 3.59 (3H, s, OCH₃), 3.89 (2H, broad, CH₂), 4.01 (2H, broad,CH₂), 4.68 and 4.91 (2H, broad, NCH₂), 7.18 (2H, m, aromatics), 7.43(2H, m, aromatics), 9.88 and 10.2 (1H, broad, OH).

EXAMPLE 215

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-.The title compound can be prepared from intermediate 101. Pale brownsolid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 12.11 (1H, s), 8.32–8.29 (1H, m),7.46–7.42 (2H, m), 7.36–7.32 (2H, m), 4.92 (1H, dd, J=14.3, 8.8 Hz),4.40 (1H, dd, J=14.1, 3.5 Hz), 3.97 (4H, s), 3.90–3.81 (1H, m),3.47–3.37 (1H, m), 3.24–3.18 (2H, m), 2.42–2.28 (2H, m), 1.97–1.86 (2H,m), 1.54 (3H, s), 1.50 (3H, s). HRMS [M+H]⁺ calcd for C₂₁H₂₇N₄SO₆:463.1651. found: 463.1669. Anal calcd for C₂₁H₂₆N₄SO₆: C, 54.53; H,5.67; N, 12.11; S, 6.93. found: C, 54.53; H, 5.41; N, 12.40; S, 6.69.

EXAMPLE 216

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.94 (1H, s), 8.86 (1H, t,J=6.2 Hz), 8.42 (1H, s), 8.16 (1H, s), 7.66 (1H, dd, J=7.3, 1.8 Hz),7.51–7.42 (2H, m), 7.35–7.32 (1H, m), 4.45 (2H, d, J=6.6 Hz), 3.98 (4H,s), 1.59 (6H, s). HRMS [M+H]⁺ calcd for C₁₉H₂₁N₆O₄: 397.1624. found:397.1609. Anal calcd for C₁₉H₂₀N₆O₄: C, 57.57; H, 5.08; N, 21.20. found:C, 57.40; H, 4.96; N, 21.09.

EXAMPLE 217

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-(3-phenylpropyl)- ¹HNMR (500 MHz, DMSO-D6) δ ppm: 1.56 (s, 6H) 1.82–1.89 (m, 2H) 2.62 (t,J=7.48 Hz, 2H) 3.31 (m, 2H) 3.82 (t, J=5.04 Hz, 2H) 3.97 (t, J=5.04 Hz,2H) 7.16–7.24 (m, 3H) 7.29 (m, 2H) 8.91 (s, 1H) δ 12.41 (s, 1H). Analcalcd for C₁₉H₂₃N₃O₄: C, 63.85; H, 6.48; N, 11.75. Found: C, 63.56; H,6.67; N, 12.01.

EXAMPLES 218–259

Examples 218–259, in table 11, were prepared using methods similar tothose described for examples 1, 19, 20. The compounds were characterizedby LCMS with the observed retention time (RT, minutes) and molecularweight (MS [M+1]) listed in the table.

TABLE 11 Example Structure RT MS 218

1.55 374.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,N-(1,3-benzodioxol-5- ylmethyl)-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 219

1.60 330.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-4-oxo-N- (phenylmethyl) 220

1.63 348.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3-fluorophenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-221

1.99 398.16 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3,4-dichlorophenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-222

1.61 360.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-N-[(3-methoxyphenyl)methyl]-9,9-dimethyl-4-oxo- 223

1.79 344.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-N-[(3-methylphenyl)methyl]-4-oxo- 224

1.65 366.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2,5-difluorophenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-225

1.27 376.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-N-[(4-hydroxy-3-methoxyphenylmethyl]-9,9-dimethyl-4- oxo- 226

1.80 364.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3-chlorophenylmethyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-227

2.00 398.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2,3-dichlorophenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-228

1.97 398.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2,5-dichlorophenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-229

1.64 390.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2,3-dimethoxyphenyl)methyl-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-230

1.64 390.24 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,N-[(2,3-dihydro-1,4- benzodioxin-6-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 231

2.01 378.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3-chloro-4-methylphenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-232

1.75 390.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2,4-dimethoxyphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 233

1.92 358.2 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2,3-dimethylphenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-234

2.01 398.0 Pyrimido[2,1-c]1,4]oxazine-2- carboxamide, N-[(3,5-dichlorophenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-235

1.71 390.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[2,5-dimethoxyphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 236

1.98 378.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3-chloro-2-methylphenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-237

1.95 416.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 238

1.70 366.0 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2,3-difluorophenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-239

1.71 394.0 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3-chloro-4-methoxyphenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-240

1.80 344.0 Pyrimido[2,1-c]1,4]oxazine-2- carboxamide, 4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-N-[(4- methylphenyl)methyl]-4-oxo-241

1.90 416.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[[4-fluoro-3-(trifluoromethyl)phenylmethyl-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 242

1.80 360.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-N-[(2-methoxyphenyl)methyl]-9,9-dimethyl-4-oxo- 243

1.90 374.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2-ethoxyphenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-244

1.60 360.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-N-[(4-methoxyphenyl)methyl]-9,9-dimethyl-4-oxo- 245

1.23 378.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(4-fluoro-3-methoxyphenyl)methyl]-4,6,7,9- tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-246

1.99 416.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 247

1.98 376.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3-ethyl-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-248

1.83 362.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3-fluoro-4-methylphenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-249

1.77 374.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(3-ethoxyphenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-250

1.59 372.0 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,N-[(2,3-dihydro-5- benzofuranyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 251

1.96 378.1 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(5-chloro-2-methylphenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-252

1.50 396.27 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-4-oxo-N-[[3-(1H-pyrazol-1-yl)phenyl]methyl] 253

1.27 415.29 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-N-[[4-(4-morpholinyl)phenyl]methyl]-4-oxo- 254

1.12 413.31 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-9,9-dimethyl-4-oxo-N-[[2-(1-piperidinyl)phenyl]methyl] 255

1.05 345.26 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(2-aminophenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-256

0.98 345.25 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[(4-aminophenyl)methyl]-4,6,7,9-tetrahydro- 3-hydroxy-9,9-dimethyl-4-oxo-257

0.98 373.29 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide, N-[[4-(dimethylamino)phenylmethyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo- 258

1.44 346.24 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-N-[(2-hydroxyphenyl)methyl]-9,9-dimethyl-4-oxo- 259

1.22 346.24 Pyrimido[2,1-c][1,4]oxazine-2- carboxamide,4,6,7,9-tetrahydro-3- hydroxy-N-[(4-hydroxyphenyl)methyl]-9,9-dimethyl-4-oxo-

EXAMPLES 260–278

Examples 260–278 were prepared according to the methods used for thepreparation of the compounds in table 3 and characterized by LCMS.

EXAMPLE 260

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(4-morpholinyl)phenyl]methyl]-4-oxo-.LCMS: HPLC retention time=4.03 min, MS=[M+1] 415.23.

EXAMPLE 261

1-piperazinecarboxylic acid,4-[2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,1,1-dimethylethyl ester. LCMS: HPLC retention time=4.93 min, MS=[M+1]514.24.

EXAMPLE 262

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(1-methylethoxy)phenyl]methyl]-4-oxo-.LCMS: HPLC retention time=4.66 min, MS=[M+1] 388.21.

EXAMPLE 263

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[3-(1-methylethoxy)phenyl]methyl]-4-oxo-.LCMS: HPLC retention time=3.97 min., MS [M+1] 4388.21.

EXAMPLE 264

Benzoic acid,3-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]-,methyl ester. LCMS: HPLC retention time=3.97 min, MS=[M+1] 388.18.

EXAMPLE 265

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-cyanophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=3.59 min, MS=[M+1] 355.2.

EXAMPLE 266

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-chloro-2-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.47 min, MS=[M+1] 382.14.

EXAMPLE 267

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,3-dihydro-1,4-benzodioxin-5-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.15 min, MS=[M+1] 388.2.

EXAMPLE 268

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dihydro-2H-1,5-benzodioxepin-6-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.12 min, MS=[M+1] 402.21.

EXAMPLE 269

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,5-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.64 min, MS=[M+1] 358.22

EXAMPLE 270

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(5-chloro-2-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.44 min, MS=[M+1] 382.15

EXAMPLE 271

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,4-dichlorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.88 min, MS=[M+1] 398.11.

EXAMPLE 272

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-chloro-2-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.69 min, MS=[M+1] 378.17.

EXAMPLE 273

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-chloro-6-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.39 min, MS=[M+1] 382.13.

EXAMPLE 274

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(6-chloro-2-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.74 min, MS=[M+1] 396.14.

EXAMPLE 275

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,6-difluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.49 min, MS=[M+1] 380.18.

EXAMPLE 276

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,3-difluoro-4-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.53 min, MS=[M+1] 380.18.

EXAMPLE 277

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-chloro-2-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.57 min, MS=[M+1] 382.13.

EXAMPLE 278

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-chloro-6-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.68 min, MS=[M+1] 396.16.

EXAMPLE 279

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[(1-methyl-1H-indol-4-yl)methyl]-4-oxo-.¹H NMR (500 MHz, DMSO-d₆) δ ppm: 1.56 (s, 6), 3.79 (s, 3), 3.82 (m, 2),3.97 (m, 2), 4.76 (d, 2), 6.62 (d, 1), 6.96 (d, 1), 7.12 (m, 1),7.27–7.38 (overlapping m, 2). HRMS [M+1] calcd for C₂₀H₂₃N₄O₄, 383.1641.found, 383.1717. Anal calcd for C₂₀H₂₂N₄O₄: C, 62.81; H, 5.79; N, 14.65.Found: C, 62.88; H, 6.08; N, 13.56.

EXAMPLE 280

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(2-oxo-1-azetidinyl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (1H, s), 9.28 (1H, broad s), 7.37 (1H,dd, J=8.2, 6.7 Hz), 7.23 (1H, dd, J=10.2, 2.4 Hz), 7.04 (1H, m), 4.51(2H, broad s), 4.35 (2H, broad s), 3.79 (2H, t, J=4.4 Hz), 3.62 (2H, m),3.11 (2H, t, J=4.4 Hz), 1.81 (2H, m), 1.55 (6H, s). LCMS (M+H)⁺ m/z 431.

EXAMPLE 281

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,dimethyl ester. Hydrogenation of dimethyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate(0.030 g, 0.055 mmol) gave 0.018 g (72%) of the title compound as awhite solid ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.63 (6H, s, 2×CH₃), 3.84(3H, s, OCH₃), 3.87 (3H, s, OCH₃), 4.03 (4H, s, 2×CH₂), 4.77 (2H, d,J=6.5 Hz, NCH₂), 7.28 (1H, m, aromatic), 7.47 (1H, m, aromatic), 7.65(1H, m, aromatic), 9.0 (1H, broad t, NH) 12.0 (1H, broad, OH). MS (ESI⁺)m/z 456 [M+H⁺].

EXAMPLE 282

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,monoethyl ester. The title compound can be prepared from intermediate188, ethyl hydrogen2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH₃), 1.60 (6H, s,2×CH₃), 4.02 (4H, s, 2×CH₂), 4.12 (2H, m, OCH₂), 4.83 (2H, broad, NCH₂),7.18 (1H, m, aromatic), 7.54 (2H, m, aromatics), 8.49 (1H, broad, NH).HRMS (ESI⁺) calculated for C₁₉H₂₄FN₃O₇P [M+H⁺]: 456.1336. found:456.1353.

EXAMPLE 283

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.White solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.01 (3H, t, J=7.4 Hz, CH₃),1.9–2.0 (1H, m, CH), 2.15–2.25 (1H, m, CH), 2.92 (6H, s, 2×NCH₃),3.8–3.9 (2H, m, CH₂), 4.1–4.3 (2H, m, CH₂), 4.45 (1H, m, CH), 4.84 (2H,d, J=7.1 Hz, NCH₂), 7.3 (1H, m, aromatic), 7.54 (1H, dd, J=2.8 Hz andJ=8.4 Hz, aromatic), 7.71 (1H, dd, J=5.4 Hz and J=8.6 Hz, aromatic),8.54 (1H, broad t, NH), 11.95 (1H, s, OH). HRMS (ESI⁺) calculated forC₁₉H₂₄FN₄O₆S [M+H⁺]: 455.1401. found: 455.1382.

EXAMPLE 284

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-e.White crystals; mp 213° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.04 (3H, t, J=7.3 Hz, CH₃), 1.9–2.0 (1H, m, CH), 2.25–2.35 (1H,m, CH), 2.56 (3H, s, CH₃), 3.8–3.9 (2H, m, CH₂), 4.15–4.3 (2H, m, CH₂),4.45–4.52 (3H, m, NCH₂ and CH), 7.10 (1H, dd, J=2.5 Hz and J=8.6 Hz,aromatic), 7.20 (1H, m, aromatic), 7.70 (1H, dd, J=6.1 Hz and J=8.6 Hz,aromatic), 8.35 (1H, s, CH), 8.8 (1H, broad t, NH), 12.12 (1H, s, OH).Anal. Calcd for C₂₀H₂₁FN₆O₄: C, 56.07; H, 4.94; N, 19.61. Found: C,55.84; H, 4.68; N, 19.47.

EXAMPLE 285

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.White solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.06 (3H, t, J=7.3 Hz, CH₃),1.9–2.05 (1H, m, CH), 2.25–2.35 (1H, m, CH), 2.50 (3H, s, CH₃), 3.8–3.9(2H, m, CH₂), 4.15–4.45 (4H, m, 2×CH₂), 4.47 (1H, m, CH), 7.05 (1H, dd,J=2.5 Hz and J=8.4 Hz, aromatic), 7.27 (1H, m, aromatic), 7.69 (1H, dd,J=5.9 Hz and J=8.6 Hz, aromatic), 8.03 (1H, s, CH), 8.5 (1H, broad t,NH), 11.93 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄ [M+H⁺]:429.1687. found: 429.1671.

EXAMPLE 286

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White crystals; mp 220° C. (ethyl acetate-ether). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 1.60 (6H, s, 2×CH₃), 4.02 (4H, s, 2×CH₂), 4.07 (3H, s, NCH₃),4.68 (2H, d, J=7.0 Hz, NCH₂), 6.53 (1H, d, J=2.5 Hz, CH), 7.04 (1H, m,aromatic), 7.28 (1H, dd, J=2.5 Hz and J=9.6 Hz, aromatic), 7.50 (1H, d,J=2.5 Hz, CH), 7.58 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 9.05 (1H,broad t, NH), 12.44 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₃FN₅O₄[M+H⁺]: 428.1734. found: 428.1732.

EXAMPLE 287

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-White crystals; mp 221° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.61 (6H, s, 2×CH₃), 3.73 (3H, s, NCH₃), 4.04 (4H, s, 2×CH₂),4.42 (2H, d, J=6.5 Hz, NCH₂), 6.34 (1H, d, J=2.0 Hz, CH), 7.03 (1H, dd,J=2.5 Hz and J=8.6 Hz, aromatic), 7.20 (1H, m, aromatic), 7.56 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 7.58 (1H, broad t, NH), 7.63 (1H, d,J=2.0 Hz, CH), 11.86 (1H, s, OH). MS (ESI⁺) m/z 428 [M+H⁺].

EXAMPLE 288

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4-oxo-e.White crystals; mp 234° C. (dec.) (ethanol). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.64 (6H, s, 2×CH₃), 2.58 (3H, s, CH₃), 4.03 (4H, s, 2×CH₂), 4.52(2H, d, J=6.8 Hz, NCH₂), 7.32–7.38 (H, m, aromatic), 7.44–7.53 (2H, m,aromatics), 7.68–7.75 (1H, m, aromatic), 8.33 (1H, s, CH), 8.81 (1H,broad t, NH), 12.17 (1H, s, OH). Anal. Calcd for C₂₀H₂₂N₆O₄: C, 58.52;H, 5.40; N, 20.47. Found: C, 58.77; H, 5.50; N, 20.20.

EXAMPLE 289

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-.Hydrogenolysis of benzyl hydrogen2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonategave the title acid as a white solid (63% yield). ¹H NMR 400 MHz(DMSO-d₆) δ (ppm): 1.53 (6H, s, 2×CH₃), 3.81 (2H, broad t, CH₂), 3.96(2H, broad t, CH₂), 4.74 (2H, d, J=6.1 Hz, NCH₂), 7.2–7.5 (3H, m,aromatics), 9.7 (1H, broad, NH), 12.18 (broad, OH). HRMS (ESI⁺)calculated for C₁₇H₂₀FN₃O₇P [M+H⁺]: 428.1023. found: 428.1005.

EXAMPLE 290

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,monomethyl ester. White solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.60 (6H,s, 2×CH₃), 3.74 and 3.77 (3H, 2 s, OCH₃), 4.02 (4H, s, 2×CH₂), 4.80 (2H,broad d, NCH₂), 7.2–7.27 (1H, m, aromatic), 7.53–7.64 (2H, m,aromatics), 8.46 (1H, broad t, NH), 11.94 (broad, OH). HRMS (ESI⁺)calculated for C₁₈H₂₂FN₃O₇P [M+H⁺]: 442.1179. found: 442.1177.

EXAMPLE 291

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-oxido-1,3,2-dioxaphospholan-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-White solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.63 (6H, s, 2×CH₃), 4.02(4H, s, 2×CH₂), 4.4–4.5 (2H, m, CH₂), 4.65–4.72 (2H, m, CH₂), 4.80 (2H,d, J=6.5 Hz, NCH₂), 7.25–7.42 (2H, m, aromatics), 7.65–7.75 (1H, m,aromatic), 9.07 (1H, broad t, NH), 11.96 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₉H₂₂FN₃O₇P [M+H⁺]: 454.1179. found: 454.1183.

EXAMPLE 292

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,mono(2-hydroxyethyl) ester. White solid ¹HNMR 400 MHz (CDCl₃) δ (ppm):1.59 (6H, s, 2×CH₃), 3.87 (2H, broad, CH₂), 4.02 (4H, s, 2×CH₂), 4.18(2H, broad, CH₂), 4.86 (2H, broad d, NCH₂), 7.16–7.24 (1H, m, aromatic),7.48–7.63 (2H, m, aromatics), 8.49 (1H, broad t, NH). HRMS (ESI⁺)calculated for C₁₉H₂₄FN₃O₈P [M+H⁺]: 472.1285. found: 472.1276.

EXAMPLE 293

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,bis(2-hydroxyethyl) ester. White solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm):1.62 (6H, s, 2×CH₃), 3.85–3.95 (4H, m, 2×CH₂), 4.03 (4H, s, 2×CH₂),4.3–4.35 (4H, m, 2×CH₂), 4.81 (2H, d, J=6.6 Hz, NCH₂), 7.27–7.32 (1H, m,aromatic), 7.5–7.7 (2H, m, aromatics), 8.93 (1H, broad t, NH), 11.97(1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₈FN₃O₉P [M+H⁺]: 516.1547.found: 516.1525.

EXAMPLE 294

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphorinan-2-yl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-White solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.17 (3H, s, CH₃), 1.19 (3H,s, CH₃), 1.62 (6H, s, 2×CH₃), 4.01 (2H, dd, J=11.1 Hz and J=13.6 Hz,CH₂), 4.03 (4H, s, 2×CH₂), 4.42 (2H, broad t, J=11 Hz, CH₂), 4.83 (2H,d, J=6.6 Hz, NCH₂), 7.27–7.33 (1H, m, aromatic), 7.45–7.55 (1H, m,aromatic), 7.65–7.75 (1H, m, aromatic), 8.81 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₂H₂₈FN₃O₇P [M+H⁺]: 496.1649. found: 496.1647.

EXAMPLE 295

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR 400 MHz (CDCl₃) δ (ppm): 8.31 (1H, s), 7.84 (1H, s), 7.58 (1H,m), 7.23 (2H, m), 4.32 (2H, s), 3.90 (2H, m), 3.81 (2H, m), 1.48 (6H,s). HRMS (ESI⁺) calculated for C₁₉H₂₀FN₄O₆ [M+H⁺] 415.1530. found:415.1549.

EXAMPLE 296

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (400 MHz, CDCl₃) δ ppm: 11.82 (1H, s), 8.45 (1H, t, J=6.4 Hz),7.73 (1H, dd, J=8.7, 5.9 Hz), 7.69 (1H, s), 7.32 (1H, dd, J=8.1, 2.5Hz), 7.04 (1H, dd, J=8.3, 2.5 Hz), 4.28 (2H, d, J=6.6 Hz), 4.03 (4H, s),2.32 (3H, s), 1.69 (6H, s), LCMS (⁺ESI, M+H⁺) m/z 429.

EXAMPLE 297

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[4-(1,1-dimethylethyl)-1H-1,2,3-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (400 MHz, CDCl₃) δ ppm: 11.95 (1H, s), 8.82 (1H, t, J=6.6 Hz),7.72 (1H, dd, J=8.6, 6.1 Hz), 7.64 (1H, s), 7.22 (1H, td, J=8.2, 2.5Hz), 7.14 (1H, dd, J=8.6, 2.5 Hz), 4.50 (2H, d, J=6.6 Hz), 4.03 (4H, s),1.66 (6H, s), 1.46 (9H, s), MS (ESI⁺) m/e 471 [M+H⁺], HRMS (ESI⁺)calculated for C₂₃H₂₈FN₆O₄ [M+H⁺] 471.2156. found: 471.2149.

EXAMPLE 298

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (400 MHz, CDCl₃) δ ppm: 11.87 (1H, s), 8.46 (1H, t, J=6.4 Hz),7.71 (1H, dd, J=8.6, 5.8 Hz), 7.24–7.31 (1H, m), 7.01 (1H, dd, J=8.3,2.8 Hz), 4.27 (2H, d, J=6.6 Hz), 4.03 (4H, s), 2.41 (3H, s), 2.23 (3H,s), 1.68 (6H, s), LCMS (⁺ESI, M+H⁺) m/z 443.

EXAMPLE 299

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (400 MHz, CDCl₃) δ ppm: 11.90 (1H, s), 8.72 (1H, s), 7.92 (1H,s), 7.76 (1H, dd, J=8.6, 6.1 Hz), 7.23–7.28 (1H, m), 7.13 (1H, dd,J=8.3, 2.5 Hz), 4.98 (2H, s), 4.47 (2H, d, J=6.8 Hz), 4.04 (4H, s), 1.67(6H, s), LCMS (⁺ESI, M+H⁺) m/z 445.

EXAMPLE 300

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR (400 MHz, CDCl₃) δ ppm: 11.94 (1H, s), 8.70 (1H, t, J=6.1 Hz),7.97 (1H, s), 7.96 (1H, s), 7.78 (1H, dd, J=8.6, 6.1 Hz), 7.22–7.28 (1H,m), 7.14 (1H, dd, J=8.3, 2.5 Hz), 4.58 (2H, s), 4.46 (2H, d, J=6.6 Hz),3.70 (2H, t, J=6.4 Hz), 1.93–1.99 (2H, m), 1.69 (6H, m), HRMS (ESI⁺)calculated for C₂₀H₂₂FN₆O₄ [M+H⁺] 429.1687. found: 429.1695.

EXAMPLE 301

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[2-[4-(1,1-dimethylethyl)-1H-1,2,3-triazol-1-yl]-4-fluorophenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR 400 MHz (CDCl₃) δ (ppm): 8.73 (1H, s), 7.74 (1H, dd, J=8.6, 6.1Hz), 7.65 (1H, s), 7.20–7.29 (1H, m), 7.15 (1H, dd, J=8.6, 2.5 Hz), 4.58(2H, br s,), 4.51 (2H, d, J=6.6 Hz), 3.69 (2H, t, J=6.3 Hz), 1.96 (2H,m), 1.66 (6H, s), 1.46 (9H, s).

EXAMPLE 302

4H-Pyrimido[1,2-d][1,4]oxazepine-2-carboxamide,N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-6,7,9,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR (400 MHz, CDCl₃) δ ppm: 11.87 (1H, s), 8.50 (1H, t, J=6.6 Hz),7.73 (1H, dd, J=8.7, 5.9 Hz), 7.28 (1H, td, J=8.3, 2.7 Hz), 7.01 (1H,dd, J=8.3, 2.5 Hz), 4.63 (2H, brs), 4.27 (2H, d, J=6.6 Hz), 3.81 (2H,brs), 3.62 (2H, s), 2.40 (3H, s), 2.23 (3H, s), 1.49 (6H, s), LCMS(⁺ESI, M+H⁺) m/z 457.

EXAMPLE 303

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.In an open vessel, acetic hydrazine (0.407 g, 5.50 mmol) was dissolvedin acetonitrile (2 mL) and dimehylformamide dimethyl acetal (0.732 g,5.50 mmol) was added. The reaction mixture was warmed to 50° C. for 0.5h. and thenN-(2-amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.091 g, 0.20 mmol) in acetonitrile (1 mL) was added followed by aceticacid (3 mL). The reaction mixture was heated at 120° C. for 3 h. Thesolvents were removed in vacuo, and the organic material dissolved inEtOAc (50 mL). The organic solution was washed with H₂O, dried (MgSO₄)and concentrated in vacuo. The crude material was dissolved in ethylacetate (10 mL), palladium 10% on charcoal (50 mg) was added and thereaction mixture was stirred under and a hydrogen atmosphere (balloon)for 2 h. Then palladium on charcoal was removed by filtration and thesolvent was removed in vacuo. The crude material was purified bycrystallization in EtOAc:Hex (4:1) to afford 0.045 g (56%) of the titlecompound as a white solid. ¹H NMR 400 MHz (CDCl₃) δ (ppm): 8.40 (1H, s),7.64–7.75 (H, m), 7.36 (1H, m), 7.05 (1H, dd, J=7.7, 2.7 Hz), 4.30 (2H,m), 4.04 (4H, s), 2.43 (3H, s), 1.62 (6H, s).

EXAMPLE 304

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR 400 MHz (MeOD) δ (ppm): 7.55 (1H, dd, J=8.6, 6.3 Hz), 7.25 (1H,dd, J=9.5, 2.7 Hz), 7.14 (1H, td, J=8.4, 2.7 Hz), 4.52–4.63 (6H, m),4.12 (2H, m), 3.72 (2H, t, J=6.3 Hz), 1.92–1.99 (2H, m), 1.63 (6H, s).HRMS (ESI⁺) calculated for C₂₁H₂₄FN₄O₆ [M+H⁺] 447.1680. found: 447.1686.

EXAMPLE 305

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(ethylsulfonyl)amino]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR 400 MHz (CDCl₃) δ (ppm): 11.36 (1H, s), 8.71 (1H, s), 8.14 (1H,m), 7.39 (1H, dd, J=8.6, 6.3 Hz), 7.28 (1H, m), 6.90 (1H, td, J=8.1, 2.5Hz), 4.60 (2H, d, J=7.1 Hz), 4.04 (4H, s), 3.25 (2H, q, J=7.3 Hz), 1.57(6H, s), 1.45 (3H, t, J=7.5 Hz).

EXAMPLE 306

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1H-pyrazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White crystalline powder: HPLC: 2.45 min (AP 98% at 254 nm); LC/MS m/z414 (M+H); ¹H NMR (CDCl₃, 500 MHz) δ ppm 1.61 (6H, s, 10,11-CH₃), 4.00(4H, s, 7,8-CH₂), 4.46 (2H, d, J=6.7 Hz, 13-CH₂), 6.54 (1H, d, J=1.5 Hz,21-CH), 7.06 (1H, dd, J=9, 2.3 Hz, 16-CH), 7.09 (1H, dt, J=8, 2.5 Hz,18-CH), 7.61 (1H, dd, J=8.1, 6.3 Hz, 19-CH), 7.77 (2H, d, J=1.2 Hz,20,21-CH), 9.17 (1H, t, J=6.0 Hz, NH), 12.07 (1H, s, OH); ¹³C NMR(CDCl₃, 125.8 Hz) δ ppm 28.0 (10,11-CH₃), 39.6 (13-CH₂), 43.1 (7-CH₂),58.3 (8-CH₂), 75.9 (9-C), 107.9 (21-CH), 112.0 (d, J=25 Hz, 16-CH),115.3 (d, J=21 Hz, 18-CH), 126.1 (4-C), 128.2 (d, J=3 Hz, 14-C), 130.5(20-CH), 134.0 (d, J=8.9 Hz, 19-CH), 140.9 (d, J=11 Hz, 15-C), 141.4(22-CH), 146.2 (5-C), 151.3 (2-C), 158.0 (6-C), 162.2 (d, J=249 Hz,17-CF), 167.7 (12-C═O); HRMS (ESI) calcd for C₂₀H₂₁FN₅O₄ (M+H) 414.1578.found 414.1578 (□ +0.1 ppm); UV (MeOH) λmax 245 nm (ε 1.90×10⁴), 306 nm(ε 7.82×10⁴); Anal. calcd for C₂₀H₂₀FN₅O₄: C, 58.10; H, 4.87; N, 16.94.found C, 57.91; H, 4.58; N, 16.85.

EXAMPLE 307

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Off-white crystalline powder. HPLC rt=1.69 min. LC/MS m/z 443 (M+H). ¹HNMR (CDCl₃, 500 MHz) δ ppm 1.61 (6H, s, 10,11-CH₃), 2.41 (3H, s,22-CH₃), 2.45 (3H, s, 23-CH₃), 3.99 (4H, s, 7,8-CH₂), 4.31 (2H, d, J=6.7Hz, 13-CH₂), 6.98 (1H, dd, J=8.4, 2.6 Hz, 16-CH), 7.16–7.23 (1H, dt,J=8.5, 2.5 Hz, 18-CH), 7.65 (1H, dd, J=8.7, 6.0 Hz, 19-CH), 8.40 (1H, t,J=6.4 Hz, NH), 11.99 (1H, s, OH). ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm 12.7(22-CH₃), 14.0 (23-CH₃), 28.1 (10,11-CH₃), 38.7 (13-CH₂), 43.1 (7-CH₂),58.2 (8-CH₂), 75.9 (9-C), 114.2 (d, J=24 Hz, 16-CH), 117.3 (d, J=21 Hz,18-CH), 125.6 (4-C), 130.8 (d, J=3.8 Hz, 14-C), 133.3 (d, J=8.8 Hz,19-CH), 137.1 (d, J=9.6 Hz, 15-C), 146.4 (5-C), 151.6 (2-C), 153.9(20-C), 158.0 (6-C), 160.7 (21-C), 161.9 (d, J=251 Hz, 17-CF), 168.1(12-C═O). HRMS (ESI) calcd for C₂₁H₂₄FN₆O₄ (M+H) 443.1843. found443.1826 (□ −3.9 ppm). UV (MeOH) λmax 316 nm (ε 7.61×10³). Anal. calcdfor C₂₁H₂₃FN₆O₄.0.3 EtOH: C, 56.86; H, 5.48; N, 18.42. found C, 56.49;H, 5.12; N, 18.68.

EXAMPLE 308

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.(white crystals, CH₃CN). HPLC rt=1.63 min. LC/MS m/z 445 (M+H). ¹H NMR(CDCl₃, 500 MHz) δ ppm 1.61 (6H, s, 10,11-CH₃), 2.42 (3H, br. OH?), 4.00(4H, s, 7,8-CH₂), 4.32 (2H, d, J=6.4 Hz, 13-CH₂), 4.73 (2H, s, 22-CH₂),7.21 (1H, dd, J=8.3, 2.5 Hz, 16-CH), 7.27 (1H, m, 18-CH), 7.68 (1H, dd,J=8.5, 5.8 Hz, 19-CH), 8.11 (1H, s, 21-CH), 8.53 (1H, t, J=6.5 Hz, NH),11.9 (1H, br, OH). ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm 28.0 (10,11-CH₃),38.5 (13-NCH₂), 43.1 (7-NCH₂), 55.0 (22-OCH₂), 58.3 (8-OCH₂), 75.9(9-C), 114.7 (d, J=25 Hz, 16-CH), 118.1 (d, J=20 Hz, 18-CH), 125.6(4-C), 130.9 (d, J=3.9 Hz, 14-C), 133.4 (d, J=9.6 Hz, 19-CH), 136.4 (d,J=9.6 Hz, 15-C), 146.3 (5-C), 150.9 (21-CH), 151.7 (2-C), 156.0 (20-C),157.9 (6-C), 162.0 (d, J=252 Hz, 17-CF), 168.0 (12-C═O). HRMS (ESI)calcd for C₂₀H₂₂FN₆O₅ (M+H) 445.1636. found 445.1630. UV (MeOH) λ max316 nm (F 8.06×10³). Anal. calcd for C₂₀H₂₁FN₆O₅.0.3H₂O: C, 53.40; H,4.84; Ni, 8.68. found C, 53.15; H, 4.61; N, 18.44. The amorphous powderwas crystallized from acetonitrile to obtain an acetonitrile solvate aswhite crystals: HPLC rt=1.65 min. LC/MS m/z 445 (M+H). ¹H NMR (CDCl₃,500 MHz) δ ppm 1.61 (6H, s, 10,11-CH₃), 2.00 (3H, s, CH₃CN), 4.00 (4H,s, 7,8-CH₂), 4.32 (2H, d, J=6.4 Hz, 13-CH₂), 4.73 (2H, s, 22-CH₂), 7.21(1H, dd, J=8.3, 2.5 Hz, 16-CH), 7.27 (1H, m, 18-CH), 7.68 (1H, dd,J=8.5, 5.8 Hz, 19-CH), 8.11 (1H, s, 21-CH), 8.53 (1H, t, J=6.5 Hz, NH),11.9 (1H, br, OH). ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm 1.97 (CH₃CN), 28.0(10,11-CH₃), 38.5 (13-NCH₂), 43.1 (7-NCH₂), 55.0 (22-OCH₂), 58.3(8-OCH₂), 75.9 (9-C), 114.7 (d, J=25 Hz, 16-CH), 116.4 (CH₃CN), 118.1(d, J=20 Hz, 18-CH), 125.6 (4-C), 130.9 (d, J=3.9 Hz, 14-C), 133.4 (d,J=9.6 Hz, 19-CH), 136.4 (d, J=9.6 Hz, 15-C), 146.3 (5-C), 150.9 (21-CH),151.7 (2-C), 156.0 (20-C), 157.9 (6-C), 162.0 (d, J=252 Hz, 17-CF),168.0 (12-C═O).

EXAMPLE 309

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[[2-(acetyloxy)ethyl]thio]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.55 (s, 6H) 1.99 (s, 3H) 3.04–3.28(m, 2H) 3.98 (s, 4H) 4.12–4.33 (m, 2H) 4.47–4.73 (m, 2H) 6.81–6.99 (m,1H) 7.03–7.43 (m, 2H) 7.90–8.10 (m, 1H) 11.85 (s, 1H); HRMS calcd. forC₂₁H₂₄FN₃O₆S (M+H) 466.1448. found 466.1439.

EXAMPLE 310

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[[2-(acetyloxy)ethyl]sulfonyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.55 (s, 6H) 1.81 (s, 3H) 3.57 (t,J=6.04 Hz, 2H) 3.97 (s, 4H) 4.44 (t, J=6.04 Hz, 2H) 4.77 (d, J=6.95 Hz,2H) 7.27–7.42 (m, 1H) 7.58–7.79 (m, 2H) 8.52 (t, J=6.77 Hz, 1H) 11.69(s, 1H)); HRMS calcd. for C₂₁H₂₄FN₃O₈S (M+H) 498.1346. found 498.1350.

EXAMPLE 311

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(ethylthio)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.33 (t, J=7.32 Hz, 3H) 1.55 (s,6H) 2.97 (q, J=7.32 Hz, 2H) 3.98 (s, 4H) 4.56–4.63 (d, J=6.78 Hz, 2H)6.70–7.09 (m, 2H) 7.31 (dd, J=8.42, 5.86 Hz, 1H) 8.00–8.22 (t, J=6.78Hz, 1H) 11.90 (s, 1H)); HRMS calcd. for C₁₉H₂₂FN₃O₄S (M+H) 408.1393.found 408.1385.

EXAMPLE 312

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(2-hydroxyethyl)sulfonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.56 (s, 6H) 3.25–3.58 (m, 2H) 3.97(s, 4H) 4.02–4.16 (m, 2H) 4.79 (d, J=6.59 Hz, 2H) 7.25–7.40 (m, 1H)7.58–7.82 (m, 2H) 8.42–8.62 (m, 1H) 11.67 (s, 1H)); HRMS calcd. forC₁₉H₂₂FN₃O₇S (M+H) 456.1241. found 456.1224.

EXAMPLE 313

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(2-hydroxyethyl)thio]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.56 (s, 6H) 2.02 (t, J=5.86 Hz,1H) 3.06–3.21 (m, 2H) 3.79 (q, J=6.10 Hz, 2H) 3.98 (s, 4H) 4.66 (d,J=6.22 Hz, 2H) 6.82–7.17 (m, 2H) 7.34 (dd, J=8.60, 6.04 Hz, 1H)7.99–8.17 (m, 1H) 11.86 (s, 1H)); HRMS calcd. for C₁₉H₂₂FN₃O₅S (M+H)424.1342. found 423.1332.

EXAMPLE 314

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 11.72 (1H, s), 8.57 (1H, t, J=6.6 Hz),7.75 (1H, dd, J=8.2, 2.7 Hz), 7.70 (1H, dd, J=8.5, 5.2 Hz), 7.34 (1H,dt, J=8.0, 2.6 Hz), 4.76–4.87 (2H, m), 4.12 (1H, dt, J=13.9, 3.5, 3.4Hz), 4.02 (1H, dt, J=12.4, 4.0 Hz), 3.88–3.96 (1H, m), 3.80–3.87 (1H,m), 3.17 (3H, s), 1.99–2.08 (1H, m), 1.79–1.88 (1H, m), 1.53 (3H, s),0.80 (3H, t, J=7.3 Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm 168.17, 163.12,161.11, 157.82, 151.83, 146.09, 140.74, 140.69, 135.13, 135.07, 132.80,132.77 125.63, 121.63, 121.46, 117.63, 117.44, 78.63, 58.31, 45.11,43.18, 40.31, 34.39, 25.38, 7.79. HRMS (ESI) calcd for C₁₉H₂₃N₃O₆FS(M+H) 440.1292. found 440.1301. Elem. Anal. calcd for C₁₉H₂₂N₃O₆FS: C,51.93; H, 5.13; N, 9.46; S, 7.22; F, 4.28. found: C, 51.78; H, 4.80; N,9.39; S, 7.19; F, 4.30. HPLC rt=2.27 min. Off-white solid.

EXAMPLE 315

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 11.83 (1H, s), 8.61 (1H, t, J=6.4 Hz),7.68 (1H, dd, J=8.5, 5.2 Hz), 7.50 (1H, dd, J=8.4, 2.6 Hz), 7.25–7.29(1H, m), 4.80 (2H, ddd, J=18.5, 14.4, 7.0 Hz), 4.12 (1H, dt, J=13.8, 3.5Hz), 4.02 (1H, dt, J=12.4, 3.9 Hz), 3.92 (1H, ddd, J=12.3, 8.9, 3.2 Hz),3.84 (1H, ddd, J=13.7, 9.1, 4.1 Hz), 2.90 (6H, s), 2.01–2.08 (1H, m),1.80–1.87 (1H, m), 1.53 (3H, s), 0.81 (3H, t, J=7.3 Hz); ¹³C NMR (126MHz, CDCl₃) δ ppm 168.03, 162.70, 160.69, 157.89, 151.63, 146.05,138.56, 138.52, 135.17, 135.11, 132.65, 132.62, 125.81, 120.37, 120.21,116.92, 116.73, 78.67, 58.34, 43.16, 40.28, 37.58, 34.39, 25.35, 7.80.HRMS (ESI) calcd for C₂₀H₂₆N₄O₆FS (M+H) 469.1557. found 469.1554. HPLCrt=2.52 min. Off-white solid.

EXAMPLE 316

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 11.88 (1H, br), 8.51 (1H, t, J=6.10 Hz),8.02 (1H, s), 7.68 (1H, dd, J=8.70, 5.95 Hz), 7.22–7.27 (1H, m), 7.02(1H, dd, J=8.24, 2.44 Hz), 4.55 (2H, br), 4.29 (2H, d, J=6.41 Hz), 3.68(2H, t, J=6.56 Hz), 2.50 (3H, s), 1.90–1.97 (2H, m), 1.64 (6H, s); ¹³CNMR (126 MHz, CDCl₃) δ ppm 168.00, 163.00, 161.01, 158.24, 153.64,153.50, 150.58, 147.36, 133.63, 133.55, 130.81, 130.78, 124.85, 117.92,117.75, 114.51, 114.32, 82.47, 60.89, 38.73, 38.63, 27.76, 27.37, 12.63.HRMS (ESI) calcd for C₂₁H₂₄N₆O₄F (M+H) 443.1843. found 443.1826. HPLCrt=1.94 min. White crystalline solid

EXAMPLE 317

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(3-methyl-H-1,2,4-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 12.08 (1H, br), 8.58–8.68 (1H, m), 8.31(1H, s), 7.66–7.73 (1H, m), 7.14–7.21 (1H, m), 7.05–7.11 (1H, m), 4.55(2H, br), 4.47 (2H, d, J=6.71 Hz), 3.64–3.72 (2H, m), 2.52 (3H, s),1.89–1.98 (2H, m), 1.62 (6H, s). HRMS (ESI) calcd for C₂₁H₂₄N₆O₄F (M+H)443.1843. found 443.1856. HPLC rt=2.04 min. Off-white solid

EXAMPLE 318

Phosphonic acid,[5-fluoro-2-[[[(4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepin-2-yl)carbonyl]amino]methyl]phenyl]-,dimethyl ester. ¹H NMR (500 MHz, CDCl₃) δ ppm 12.02–12.11 (1H, br), 8.94(1H, t, J=6.71 Hz), 7.59–7.65 (1H, m), 7.40–7.47 (1H, m), 7.21–7.26 (1H,m), 4.74 (2H, d, J=6.71 Hz), 4.49–4.59 (2H, br), 3.81–3.83 (3H, s),3.79–3.81 (3H, s), 3.63–3.68 (2H, m), 1.89–1.96 (2H, m), 1.59–1.64 (6H,s); ¹³C NMR (126 MHz, CDCl₃) δ ppm 168.01, 158.34, 153.28, 147.32,137.64, 134.25, 134.19, 134.12, 134.06, 125.20, 120.43, 120.36, 120.25,120.18, 120.08, 82.58, 60.79, 53.26, 53.22, 41.45, 41.42, 38.53, 27.75,27.37. HRMS (ESI) calcd for C₂₀H₂₆N₃O₇FP (M+H) 470.1492. found 470.1487.Elem. Anal. calcd for C₂₀H₂₅N₃O₇FP: C, 51.17; H, 5.36; N, 8.95. found:C, 51.21; H, 5.24; N, 8.70. HPLC rt=2.09 min. White crystalline solid.

EXAMPLE 319

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR (500 MHz, CHLOROFORM-D) δ ppm 12.01 (1H, s), 8.31 (1H, t, J=6.26Hz), 7.66 (1H, dd, J=8.55, 6.10 Hz), 7.21 (1H, td, J=8.24, 2.44 Hz),6.99 (1H, dd, J=8.55, 2.44 Hz), 4.55 (2H, s), 4.32 (2H, d, J=6.71 Hz),3.67 (2H, t, J=6.41 Hz), 2.44 (3H, s), 2.42 (3H, s), 1.90–1.98 (2H, m),1.62 (6H, s); ¹³C NMR (126 MHz, CHLOROFORM-D) δ ppm 168.11, 162.95,160.95, 160.59, 158.24, 153.78, 153.45, 147.48, 137.07, 136.99, 133.42,133.35, 130.80, 124.86, 117.45, 117.29, 114.32, 114.12, 82.42, 60.83,38.65, 27.90, 27.34, 13.94, 12.71: HRMS (ESI) calcd for C₂₂H₂₆N₆O₄F(M+H) 457.2000. found 457.2018. Elem. Anal. calcd for C₂₂H₂₅N₆O₄F: C,57.54; H, 5.55; N, 18.30. found: C, 57.91; H, 5.35; N, 18.05. HPLC rt1.82 min. White solid.

1. A compound selected from the group consisting ofN-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;9-ethyl-N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;9-ethyl-N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-phosphonicacid;[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-phosphonicacid, monomethyl ester;N-[[4-fluoro-2-(2-oxido-1,3,2-dioxaphospholan-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-phosphonicacid, mono(2-hydroxyethyl) ester;[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-phosphonicacid, bis(2-hydroxyethyl) ester;N-[[2-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphorinan-2-yl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-[4-(1,1-dimethylethyl)-1H-1,2,3-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;N-[[2-[4-(1,1-dimethylethyl)-1H-1,2,3-triazol-1-yl]-4-fluorophenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-6,7,9,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo4H-pyrimido[1,2-d][1,4]oxazepine-2-carboxamide;N-[[4-fluoro-2-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;N-[[2-[(ethylsulfonyl)amino]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(1H-pyrazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-[[2-(acetyloxy)ethyl]thio]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-[[2-(acetyloxy)ethyl]sulfonyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-(ethylthio)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[(2-hydroxyethyl)sulfonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[(2-hydroxyethyl)thio]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;9-ethyl-N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;[5-fluoro-2-[[[(4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepin-2-yl)carbonyl]amino]methyl]phenyl]-phosphonicacid, dimethyl ester; andN-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.
 2. Acomposition useful for treating HIV infections comprising a therapeuticamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 3. The composition of claim 2 further comprising atherapeutically effective amount at least one other agent used fortreatment of AIDS or HIV infection selected from the group consisting ofnucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, HIV protease inhibitors, HIV fusioninhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4inhibitors, HIV budding or maturation inhibitors, and HIV integraseinhibitors, and a pharmaceutically acceptable carrier.
 4. A method fortreating HIV infection comprising administering a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, to a patient in need thereof.
 5. Themethod of claim 4 further comprising administering a therapeuticallyeffective amount of at least one other agent used for treatment of AIDSor HIV infection selected from the group consisting of nucleoside HIVreverse transcriptase inhibitors, non-nucleoside HIV reversetranscriptase inhibitors, HIV protease inhibitors, HIV fusioninhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4inhibitors, HIV budding or maturation inhibitors, and HIV integraseinhibitors.